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Results in Journal Cold Spring Harbor Perspectives in Biology: 1,492

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S. Kevin McCormick, Kay E. Holekamp, Laura Smale, Mary L. Weldele, Stephen E. Glickman, Ned J. Place
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039180

Abstract:
The apparent virilization of the female spotted hyena raises questions about sex differences in behavior and morphology. We review these sex differences to find a mosaic of dimorphic traits, some of which conform to mammalian norms. These include space-use, dispersal behavior, sexual behavior, and parental behavior. By contrast, sex differences are reversed from mammalian norms in the hyena's aggressive behavior, social dominance, and territory defense. Androgen exposure early in development appears to enhance aggressiveness in female hyenas. Weapons, hunting behavior, and neonatal body mass do not differ between males and females, but females are slightly larger than males as adults. Sex differences in the hyena's nervous system are relatively subtle. Overall, it appears that the “masculinized” behavioral traits in female spotted hyenas are those, such as aggression, that are essential to ensuring consistent access to food; food critically limits female reproductive success in this species because female spotted hyenas have the highest energetic investment per litter of any mammalian carnivore. Evidently, natural selection has acted to modify traits related to food access, but has left intact those traits that are unrelated to acquiring food, such that they conform to patterns of sexual dimorphism in other mammals.
Irving Zucker, Brian J. Prendergast, Annaliese K. Beery
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039156

Abstract:
Females have long been underrepresented in preclinical research and clinical drug trials. Directives by the U.S. National Institutes of Health have increased female participation in research protocols, although analysis of outcomes by sex remains infrequent. The long-held view that traits of female rats and mice are more variable than those of males is discredited, supporting equal representation of both sexes in most studies. Drug pharmacokinetic analysis reveals that, among subjects administered a standard drug dose, women are exposed to higher blood drug concentrations and longer drug elimination times. This contributes to increased adverse drug reactions in women and suggests that women are routinely overmedicated and should be administered lower drug doses than men. The past decade has seen progress in female inclusion, but key subsequent steps such as sex-based analysis and sex-specific drug dosing remain to be implemented.
Ivonne Sehring,
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040758

Abstract:
The zebrafish caudal fin has become a popular model to study cellular and molecular mechanisms of regeneration due to its high regenerative capacity, accessibility for experimental manipulations, and relatively simple anatomy. The formation of a regenerative epidermis and blastema are crucial initial events and tightly regulated. Both the regenerative epidermis and the blastema are highly organized structures containing distinct domains, and several signaling pathways regulate the formation and interaction of these domains. Bone is the major tissue regenerated from the progenitor cells of the blastema. Several cellular mechanisms can provide source cells for blastemal (pre-)osteoblasts, including dedifferentiation of differentiated osteoblasts and de novo formation from other cell types, providing intriguing examples of cellular plasticity. In recent years, omics analyses and single-cell approaches have elucidated genetic and epigenetic regulation, increasing our knowledge of the surprisingly complex coordination of various mechanisms to achieve successful restoration of a seemingly simple structure.
Ya-Chieh Hsu, Elaine Fuchs
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040840

Abstract:
The skin forms a crucial, dynamic barrier between an animal and the external world. In mammals, three stem cell populations possess robust regenerative potential to maintain and repair the body's protective surface: epidermal stem cells, which maintain the stratified epidermis; hair follicle stem cells, which power the cyclic growth of the hair follicle; and melanocyte stem cells, which regenerate pigment-producing melanocytes to color the skin and hair. These stem cells reside in complex microenvironments (“niches”) comprising diverse cellular repertoires that enable stem cells to rejuvenate tissues during homeostasis and regenerate them upon injury. Beyond their niches, skin stem cells can also sense and respond to fluctuations in organismal health or changes outside the body. Here, we review these diverse cellular interactions and highlight how far-reaching signals can be transmitted at the local level to enable skin stem cells to tailor their actions to suit the particular occasion and optimize fitness.
Leo Otsuki, Elly M. Tanaka
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040899

Abstract:
Salamanders, such as axolotls and newts, can regenerate complex tissues including entire limbs. But what mechanisms ensure that an amputated limb regenerates a limb, and not a tail or unpatterned tissue? An important concept in regeneration is positional memory—the notion that adult cells “remember” spatial identities assigned to them during embryogenesis (e.g., “head” or “hand”) and use this information to restore the correct body parts after injury. Although positional memory is well documented at a phenomenological level, the underlying cellular and molecular bases are just beginning to be decoded. Herein, we review how major principles in positional memory were established in the salamander limb model, enabling the discovery of positional memory-encoding molecules, and advancing insights into their pattern-forming logic during regeneration. We explore findings in other amphibians, fish, reptiles, and mammals and speculate on conserved aspects of positional memory. We consider the possibility that manipulating positional memory in human cells could represent one route toward improved tissue repair or engineering of patterned tissues for therapeutic purposes.
Brian C. Trainor, Annegret L. Falkner
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039164

Abstract:
Sex differences are commonly observed in behaviors that are closely linked to adaptive function, but sex differences can also be observed in behavioral “building blocks” such as locomotor activity and reward processing. Modern neuroscientific inquiry, in pursuit of generalizable principles of functioning across sexes, has often ignored these more subtle sex differences in behavioral building blocks that may result from differences in these behavioral building blocks. A frequent assumption is that there is a default (often male) way to perform a behavior. This approach misses fundamental drivers of individual variability within and between sexes. Incomplete behavioral descriptions of both sexes can lead to an overreliance on reduced “single-variable” readouts of complex behaviors, the design of which may be based on male-biased samples. Here, we advocate that the incorporation of new machine-learning tools for collecting and analyzing multimodal “big behavior” data allows for a more holistic and richer approach to the quantification of behavior in both sexes. These new tools make behavioral description more robust and replicable across laboratories and species, and may open up new lines of neuroscientific inquiry by facilitating the discovery of novel behavioral states. Having more accurate measures of behavioral diversity in males and females could serve as a hypothesis generator for where and when we should look in the brain for meaningful neural differences.
Levi Todd, Thomas A. Reh
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040816

Abstract:
The regenerative capacity of the vertebrate retina varies substantially across species. Whereas fish and amphibians can regenerate functional retina, mammals do not. In this perspective piece, we outline the various strategies nonmammalian vertebrates use to achieve functional regeneration of vision. We review key differences underlying the regenerative potential across species including the cellular source of postnatal progenitors, the diversity of cell fates regenerated, and the level of functional vision that can be achieved. Finally, we provide an outlook on the field of engineering the mammalian retina to replace neurons lost to injury or disease.
Leonid Mirny, Job Dekker
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040147

Abstract:
Microscopy and genomic approaches provide detailed descriptions of the three-dimensional folding of chromosomes and nuclear organization. The fundamental question is how activity of molecules at the nanometer scale can lead to complex and orchestrated spatial organization at the scale of chromosomes and the whole nucleus. At least three key mechanisms can bridge across scales: (1) tethering of specific loci to nuclear landmarks leads to massive reorganization of the nucleus; (2) spatial compartmentalization of chromatin, which is driven by molecular affinities, results in spatial isolation of active and inactive chromatin; and (3) loop extrusion activity of SMC (structural maintenance of chromosome) complexes can explain many features of interphase chromatin folding and underlies key phenomena during mitosis. Interestingly, many features of chromosome organization ultimately result from collective action and the interplay between these mechanisms, and are further modulated by transcription and topological constraints. Finally, we highlight some outstanding questions that are critical for our understanding of nuclear organization and function. We believe many of these questions can be answered in the coming years.
Peter W. Reddien
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040717

Abstract:
The capacity for regeneration is broad in the animal kingdom. Planarians are flatworms that can regenerate any missing body part and their regenerative powers have combined with ease of experimentation to make them a classic regeneration model for more than a century. Pluripotent stem cells called neoblasts generate missing planarian tissues. Fate specification happens in the neoblasts, and this can occur in response to regeneration instructions in the form of positional information. Fate specification can lead to differentiating cells in single steps rather than requiring a long lineage hierarchy. Planarians display constitutive expression of positional information from muscle cells, which is required for patterned maintenance of tissues in tissue turnover. Amputation leads to the rapid resetting of positional information in a process triggered by wound signaling and the resetting of positional information is required for regeneration. These findings suggest a model for planarian regeneration in which adult positional information resets after injury to regulate stem cells to bring about the replacement of missing parts.
Carla C. Winter, Zhigang He, Anne Jacobi
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040923

Abstract:
Axons are a unique cellular structure that allows for the communication between neurons. Axon damage compromises neuronal communications and often leads to functional deficits. Thus, developing strategies that promote effective axon regeneration for functional restoration is highly desirable. One fruitful approach is to dissect the regenerative mechanisms used by some types of neurons in both mammalian and nonmammalian systems that exhibit spontaneous regenerative capacity. Additionally, numerous efforts have been devoted to deciphering the barriers that prevent successful axon regeneration in the most regeneration-refractory system—the adult mammalian central nervous system. As a result, several regeneration-promoting strategies have been developed, but significant limitations remain. This review is aimed to summarize historic progression and current understanding of this exciting yet incomplete endeavor.
Elizabeth S. Williams, Michelle Mazei-Robison, A.J. Robison
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039198

Abstract:
Depression and related mood disorders constitute an enormous burden on health, quality of life, and the global economy, and women have roughly twice the lifetime risk of men for experiencing depression. Here, we review sex differences in human brain physiology that may be connected to the increased susceptibility of women to major depressive disorder (MDD). Moreover, we summarize decades of preclinical research using animal models for the study of mood dysfunction that uncover some of the potential molecular, cellular, and circuit-level mechanisms that may underlie sex differences and disease etiology. We place particular emphasis on a series of recent studies demonstrating the central contribution of the circuit projecting from ventral hippocampus to nucleus accumbens and how inherent sex differences in the excitability of this circuit may predict and drive depression-related behaviors. The findings covered in this review underscore the continued need for studies using preclinical models and circuit-specific strategies for uncovering molecular and physiological mechanisms that could lead to potential sex-specific diagnosis, prognosis, prevention, and/or treatments for MDD and other mood disorders.
Andrew S. Belmont
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a041268

Abstract:
This work reviews nuclear compartments, defined broadly to include distinct nuclear structures, bodies, and chromosome domains. It first summarizes original cytological observations before comparing concepts of nuclear compartments emerging from microscopy versus genomic approaches and then introducing new multiplexed imaging approaches that promise in the future to meld both approaches. I discuss how previous models of radial distribution of chromosomes or the binary division of the genome into A and B compartments are now being refined by the recognition of more complex nuclear compartmentalization. The poorly understood question of how these nuclear compartments are established and maintained is then discussed, including through the modern perspective of phase separation, before moving on to address possible functions of nuclear compartments, using the possible role of nuclear speckles in modulating gene expression as an example. Finally, the review concludes with a discussion of future questions for this field.
Devon Davidian,
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040782

Abstract:
Limb loss due to traumatic injury or amputation is a major biomedical burden. Many vertebrates exhibit the ability to form and pattern normal limbs during embryogenesis from amorphous clusters of precursor cells, hinting that this process could perhaps be activated later in life to rebuild missing or damaged limbs. Indeed, some animals, such as salamanders, are proficient regenerators of limbs throughout their life span. Thus, research over the last century has sought to stimulate regeneration in species that do not normally regenerate their appendages. Importantly, these efforts are not only a vital aspect of regenerative medicine, but also have fundamental implications for understanding evolution and the cellular control of growth and form throughout the body. Here we review major recent advances in augmenting limb regeneration, summarizing the degree of success that has been achieved to date in frog and mammalian models using genetic, biochemical, and bioelectrical interventions. While the degree of whole limb repair in rodent models has been modest to date, a number of new technologies and approaches comprise an exciting near-term road map for basic and clinical progress in regeneration.
Jiří Friml
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039859

Abstract:
Auxin has always been at the forefront of research in plant physiology and development. Since the earliest contemplations by Julius von Sachs and Charles Darwin, more than a century-long struggle has been waged to understand its function. This largely reflects the failures, successes, and inevitable progress in the entire field of plant signaling and development. Here I present 14 stations on our long and sometimes mystical journey to understand auxin. These highlights were selected to give a flavor of the field and to show the scope and limits of our current knowledge. A special focus is put on features that make auxin unique among phytohormones, such as its dynamic, directional transport network, which integrates external and internal signals, including self-organizing feedback. Accented are persistent mysteries and controversies. The unexpected discoveries related to rapid auxin responses and growth regulation recently disturbed our contentment regarding understanding of the auxin signaling mechanism. These new revelations, along with advances in technology, usher us into a new, exciting era in auxin research.
Xianrong Wong, Ashley J. Melendez-Perez, Karen L. Reddy
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040113

Abstract:
Lamins interact with a host of nuclear membrane proteins, transcription factors, chromatin regulators, signaling molecules, splicing factors, and even chromatin itself to form a nuclear subcompartment, the nuclear lamina, that is involved in a variety of cellular processes such as the governance of nuclear integrity, nuclear positioning, mitosis, DNA repair, DNA replication, splicing, signaling, mechanotransduction and -sensation, transcriptional regulation, and genome organization. Lamins are the primary scaffold for this nuclear subcompartment, but interactions with lamin-associated peptides in the inner nuclear membrane are self-reinforcing and mutually required. Lamins also interact, directly and indirectly, with peripheral heterochromatin domains called lamina-associated domains (LADs) and help to regulate dynamic 3D genome organization and expression of developmentally regulated genes.
Asli Yildirim, Lorenzo Boninsegna, Yuxiang Zhan, Frank Alber
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039693

Abstract:
Our understanding of how genomic DNA is tightly packed inside the nucleus, yet is still accessible for vital cellular processes, has grown dramatically over recent years with advances in microscopy and genomics technologies. Computational methods have played a pivotal role in the structural interpretation of experimental data, which helped unravel some organizational principles of genome folding. Here, we give an overview of current computational efforts in mechanistic and data-driven 3D chromatin structure modeling. We discuss strengths and limitations of different methods and evaluate the added value and benefits of computational approaches to infer the 3D structural and dynamic properties of the genome and its underlying mechanisms at different scales and resolution, ranging from the dynamic formation of chromatin loops and topological associated domains to nuclear compartmentalization of chromatin and nuclear bodies.
Zhenhai Du, Ke Zhang, Wei Xie
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039677

Abstract:
Dramatic nuclear reorganization occurs during early development to convert terminally differentiated gametes to a totipotent zygote, which then gives rise to an embryo. Aberrant epigenome resetting severely impairs embryo development and even leads to lethality. How the epigenomes are inherited, reprogrammed, and reestablished in this critical developmental period has gradually been unveiled through the rapid development of technologies including ultrasensitive chromatin analysis methods. In this review, we summarize the latest findings on epigenetic reprogramming in gametogenesis and embryogenesis, and how it contributes to gamete maturation and parental-to-zygotic transition. Finally, we highlight the key questions that remain to be answered to fully understand chromatin regulation and nuclear reprogramming in early development.
Sofia A. Quinodoz, Mitchell Guttman
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039719

Abstract:
It has long been proposed that nuclear RNAs might play an important role in organizing the structure of the nucleus. Initial experiments performed more than 30 years ago found that global disruption of RNA led to visible rearrangements of nuclear organization. Yet, this idea remained controversial for many years, in large part because it was unclear what specific RNAs might be involved, and which specific nuclear structures might be dependent on RNA. Over the past few years, the contributions of RNA to organizing nuclear structures have become clearer with the discovery that many nuclear bodies are enriched for specific noncoding RNAs (ncRNAs); in specific cases, ncRNAs have been shown to be essential for establishment and maintenance of these nuclear structures. More recently, many different ncRNAs have been shown to play critical roles in initiating the three-dimensional (3D) spatial organization of DNA, RNA, and protein molecules in the nucleus. These examples, combined with global imaging and genomic experiments, have begun to paint a picture of a broader role for RNA in nuclear organization and to uncover a unifying mechanism that may explain why RNA is a uniquely suited molecule for this role. In this review, we provide an overview of the history of RNA and nuclear structure and discuss key examples of RNA-mediated bodies, the global roles of ncRNAs in shaping nuclear structure, and emerging insights into mechanisms of RNA-mediated nuclear organization.
Peng Zhang, Bruce A. Edgar
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040915

Abstract:
In adult insects, as in vertebrates, the gut epithelium is a highly regenerative tissue that can renew itself rapidly in response to changing inputs from nutrition, the gut microbiota, ingested toxins, and signals from other organs. Because of its cellular and genetic similarities to the mammalian intestine, and its relevance as a target for the control of insect pests and disease vectors, many researchers have used insect intestines to address fundamental questions about stem cell functions during tissue maintenance and regeneration. In Drosophila, where most of the experimental work has been performed, not only are intestinal cell types and behaviors well characterized, but numerous cell signaling interactions have been detailed that mediate gut epithelial regeneration. A prevailing model for regenerative responses in the insect gut invokes stress sensing by damaged enterocytes (ECs) as a principal source for signaling that activates the division of intestinal stem cells (ISCs) and the growth and differentiation of their progeny. However, extant data also reveal alternative mechanisms for regeneration that involve ISC-intrinsic functions, active culling of healthy epithelial cells, enhanced EC growth, and even cytoplasmic shedding by infected ECs. This article reviews current knowledge of the molecular mechanisms involved in gut regeneration in several insect models (Drosophila and Aedes of the order Diptera, and several Lepidoptera).
Juliane Glaser, Stefan Mundlos
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040188

Abstract:
One of the most fundamental questions in developmental biology is how one fertilized cell can give rise to a fully mature organism and how gene regulation governs this process. Precise spatiotemporal gene expression is required for development and is believed to be achieved through a complex interplay of sequence-specific information, epigenetic modifications, trans-acting factors, and chromatin folding. Here we review the role of chromatin folding during development, the mechanisms governing 3D genome organization, and how it is established in the embryo. Furthermore, we discuss recent advances and debated questions regarding the contribution of the 3D genome to gene regulation during organogenesis. Finally, we describe the mechanisms that can reshape the 3D genome, including disease-causing structural variations and the emerging view that transposable elements contribute to chromatin organization.
Gemma L. Johnson, Jessica A. Lehoczky
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040857

Abstract:
In this review, we present the current state of knowledge surrounding mammalian digit tip regeneration. We discuss the origin and formation of the blastema, a structure integral to digit tip regeneration, as well as recent insights driven by single-cell RNA sequencing into the molecular markers and cellular composition of the blastema. The digit tip is a composite of many different tissue types and we address what is known about the role of these separate tissues in regeneration of the whole digit tip. Specifically, we discuss the most extensively studied tissues in the digit tip: bone, nail epithelium, and peripheral nerves. We also address how known molecular pathways in limb development can inform research into digit tip regeneration. Overall, the mouse digit tip is an excellent model of complex mammalian regeneration that can provide insight into inducing regeneration in human tissues.
Suruchi Roychoudhry, Stefan Kepinski
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039933

Abstract:
Root system architecture is an important determinant of below-ground resource capture and hence overall plant fitness. The plant hormone auxin plays a central role in almost every facet of root development from the cellular to the whole-root-system level. Here, using Arabidopsis as a model, we review the multiple gene signaling networks regulated by auxin biosynthesis, conjugation, and transport that underpin primary and lateral root development. We describe the role of auxin in establishing the root apical meristem and discuss how the tight spatiotemporal regulation of auxin distribution controls transitions between cell division, cell growth, and differentiation. This includes the localized reestablishment of mitotic activity required to elaborate the root system via the production of lateral roots. We also summarize recent discoveries on the effects of auxin and auxin signaling and transport on the control of lateral root gravitropic setpoint angle (GSA), a critical determinant of the overall shape of the root system. Finally, we discuss how environmental conditions influence root developmental plasticity by modulation of auxin biosynthesis, transport, and the canonical auxin signaling pathway.
Marcela Raices, Maximiliano A. D'Angelo
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040691

Abstract:
In eukaryotic cells, the genetic material is segregated inside the nucleus. This compartmentalization of the genome requires a transport system that allows cells to move molecules across the nuclear envelope, the membrane-based barrier that surrounds the chromosomes. Nuclear pore complexes (NPCs) are the central component of the nuclear transport machinery. These large protein channels penetrate the nuclear envelope, creating a passage between the nucleus and the cytoplasm through which nucleocytoplasmic molecule exchange occurs. NPCs are one of the largest protein assemblies of eukaryotic cells and, in addition to their critical function in nuclear transport, these structures also play key roles in many cellular processes in a transport-independent manner. Here we will review the current knowledge of the NPC structure, the cellular mechanisms that regulate their formation and maintenance, and we will provide a brief description of a variety of processes that NPCs regulate.
François Dossin, Edith Heard
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040196

Abstract:
In female eutherian mammals, dosage compensation of X-linked gene expression is achieved during development through transcriptional silencing of one of the two X chromosomes. Following X chromosome inactivation (XCI), the inactive X chromosome remains faithfully silenced throughout somatic cell divisions. XCI is dependent on Xist, a long noncoding RNA that coats and silences the X chromosome from which it is transcribed. Xist coating triggers a cascade of chromosome-wide changes occurring at the levels of transcription, chromatin composition, chromosome structure, and spatial organization within the nucleus. XCI has emerged as a paradigm for the study of such crucial nuclear processes and the dissection of their functional interplay. In the past decade, the advent of tools to characterize and perturb these processes have provided an unprecedented understanding into their roles during XCI. The mechanisms orchestrating the initiation of XCI as well as its maintenance are thus being unraveled, although many questions still remain. Here, we introduce key aspects of the XCI process and review the recent discoveries about its molecular basis.
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040725

Abstract:
Here we discuss the developmental and homeostatic conditions necessary for Hydra regeneration. Hydra is characterized by populations of adult stem cells paused in the G2 phase of the cell cycle, ready to respond to injury signals. The body column can be compared to a blastema-like structure, populated with multifunctional epithelial stem cells that show low sensitivity to proapoptotic signals, and high inducibility of autophagy that promotes resistance to stress and starvation. Intact Hydra polyps also exhibit a dynamic patterning along the oral–aboral axis under the control of homeostatic organizers whose activity results from regulatory loops between activators and inhibitors. As in bilaterians, injury triggers the immediate production of reactive oxygen species (ROS) signals that promote wound healing and contribute to the reactivation of developmental programs via cell death and the de novo formation of new organizing centers from somatic tissues. In aging Hydra, regeneration is rapidly lost as homeostatic conditions are no longer pro-regenerative.
Marcelo Nollmann, Isma Bennabi, Markus Götz, Thomas Gregor
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040378

Abstract:
Over the past two decades, it has become clear that the multiscale spatial and temporal organization of the genome has important implications for nuclear function. This review centers on insights gained from recent advances in light microscopy on our understanding of transcription. We discuss spatial and temporal aspects that shape nuclear order and their consequences on regulatory components, focusing on genomic scales most relevant to function. The emerging picture is that spatiotemporal constraints increase the complexity in transcriptional regulation, highlighting new challenges, such as uncertainty about how information travels from molecular factors through the genome and space to generate a functional output.
Berkley Gryder, Peter C. Scacheri, Thomas Ried, Javed Khan
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040956

Abstract:
The change in cell state from normal to malignant is driven fundamentally by oncogenic mutations in cooperation with epigenetic alterations of chromatin. These alterations in chromatin can be a consequence of environmental stressors or germline and/or somatic mutations that directly alter the structure of chromatin machinery proteins, their levels, or their regulatory function. These changes can result in an inability of the cell to differentiate along a predefined lineage path, or drive a hyperactive, highly proliferative state with addiction to high levels of transcriptional output. We discuss how these genetic alterations hijack the chromatin machinery for the oncogenic process to reveal unique vulnerabilities and novel targets for cancer therapy.
Thomas A. Rando, D. Leanne Jones
Cold Spring Harbor Perspectives in Biology, Volume 13; https://doi.org/10.1101/cshperspect.a040907

Abstract:
While some animals, such as planaria and hydra, appear to be capable of seemingly endless cycles of regeneration, most animals experience a gradual decline in fitness and ultimately die. The progressive loss of cell and tissue function, leading to senescence and death, is generally referred to as aging. Adult (“tissue”) stem cells maintain tissue homeostasis and facilitate repair; however, age-related changes in stem cell function over time are major contributors to loss of organ function or disease in older individuals. Therefore, considerable effort is being invested in restoring stem cell function to counter degenerative diseases and age-related tissue dysfunction. Here, we will review strategies that could be used to restore stem cell function, including the use of environmental interventions, such as diet and exercise, heterochronic approaches, and cellular reprogramming. Maintaining optimal stem cell function and tissue homeostasis into late life will likely extend the amount of time older adults are able to be independent and lead healthy lives.
Yekaterina A. Miroshnikova, Sara A. Wickström
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039685

Abstract:
Cells generate and sense mechanical forces that trigger biochemical signals to elicit cellular responses that control cell fate changes. Mechanical forces also physically distort neighboring cells and the surrounding connective tissue, which propagate mechanochemical signals over long distances to guide tissue patterning, organogenesis, and adult tissue homeostasis. As the largest and stiffest organelle, the nucleus is particularly sensitive to mechanical force and deformation. Nuclear responses to mechanical force include adaptations in chromatin architecture and transcriptional activity that trigger changes in cell state. These force-driven changes also influence the mechanical properties of chromatin and nuclei themselves to prevent aberrant alterations in nuclear shape and help maintain genome integrity. This review will discuss principles of nuclear mechanotransduction and chromatin mechanics and their role in DNA damage and cell fate regulation.
Hui-Min Yin,
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040766

Abstract:
Heart regeneration is a remarkable process whereby regrowth of damaged cardiac tissue rehabilitates organ anatomy and function. Unfortunately, the human heart is highly resistant to regeneration, which creates a shortage of cardiomyocytes in the wake of ischemic injury, and explains, in part, why coronary artery disease remains a leading cause of death worldwide. Luckily, a detailed blueprint for achieving therapeutic heart regeneration already exists in nature because several lower vertebrate species successfully regenerate amputated or damaged heart muscle through robust cardiomyocyte proliferation. A growing number of species are being interrogated for cardiac regenerative potential, and several commonalities have emerged between those animals showing high or low innate capabilities. In this review, we provide a historical perspective on the field, discuss how regenerative potential is influenced by cardiomyocyte properties, mitogenic signals, and chromatin accessibility, and highlight unanswered questions under active investigation. Ultimately, delineating why heart regeneration occurs preferentially in some organisms, but not in others, will uncover novel therapeutic inroads for achieving cardiac restoration in humans.
Erin C. Bailey, Sara Kobielski, John Park, Vicki P. Losick
Cold Spring Harbor Perspectives in Biology, Volume 13; https://doi.org/10.1101/cshperspect.a040881

Abstract:
Polyploidy is defined as a cell with three or more whole genome sets and enables cell growth across the kingdoms of life. Studies in model organisms have revealed that polyploid cell growth can be required for optimal tissue repair and regeneration. In mammals, polyploid cell growth contributes to repair of many tissues, including the liver, heart, kidney, bladder, and eye, and similar strategies have been identified in Drosophila and zebrafish tissues. This review discusses the heterogeneity and versatility of polyploidy in tissue repair and regeneration. Polyploidy has been shown to restore tissue mass and maintain organ size as well as protect against oncogenic insults and genotoxic stress. Polyploid cells can also serve as a reservoir for new diploid cells in regeneration. The numerous mechanisms to generate polyploid cells provide an unlimited resource for tissues to exploit to undergo repair or regeneration.
Michael Chas Sumner,
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039438

Abstract:
The nuclear pore complex (NPC) is a highly conserved channel in the nuclear envelope that mediates mRNA export to the cytosol and bidirectional protein transport. Many chromosomal loci physically interact with nuclear pore proteins (Nups), and interactions with Nups can promote transcriptional repression, transcriptional activation, and transcriptional poising. Interaction with the NPC also affects the spatial arrangement of genes, interchromosomal clustering, and folding of topologically associated domains. Thus, the NPC is a spatial organizer of the genome and regulator of genome function.
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040683

Abstract:
In eukaryotic cells, protein and RNA factors involved in genome activities like transcription, RNA processing, DNA replication, and repair accumulate in self-organizing membraneless chromatin subcompartments. These structures contribute to efficiently conduct chromatin-mediated reactions and to establish specific cellular programs. However, the underlying mechanisms for their formation are only partly understood. Recent studies invoke liquid–liquid phase separation (LLPS) of proteins and RNAs in the establishment of chromatin activity patterns. At the same time, the folding of chromatin in the nucleus can drive genome partitioning into spatially distinct domains. Here, the interplay between chromatin organization, chromatin binding, and LLPS is discussed by comparing and contrasting three prototypical chromatin subcompartments: the nucleolus, clusters of active RNA polymerase II, and pericentric heterochromatin domains. It is discussed how the different ways of chromatin compartmentalization are linked to transcription regulation, the targeting of soluble factors to certain parts of the genome, and to disease-causing genetic aberrations.
, Weihan Li, , Robert A. Coleman
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039453

Abstract:
Within the nucleus, messenger RNA is generated and processed in a highly organized and regulated manner. Messenger RNA processing begins during transcription initiation and continues until the RNA is translated and degraded. Processes such as 5′ capping, alternative splicing, and 3′ end processing have been studied extensively with biochemical methods and more recently with single-molecule imaging approaches. In this review, we highlight how imaging has helped understand the highly dynamic process of RNA processing. We conclude with open questions and new technological developments that may further our understanding of RNA processing.
Caitlin C. Zebley, Rama S. Akondy, Benjamin A. Youngblood, Haydn T. Kissick
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a037804

Abstract:
The pool of memory CD8 T cells is comprised of highly specialized subpopulations of cells with both shared and distinct functions. The ongoing study of T-cell memory is focused on how these different subpopulations arise, how the cells are maintained over the life of the host, and how the cells protect a host against reinfection. As a field we have used the convenience of a narrow range of surface markers to define and study these memory T-cell subsets. However, as we learn more about these cells, it is becoming clear that these broad definitions are insufficient to capture the complexity of the CD8 memory T-cell pool, and an updated definition of these cellular states are needed. Here, we discuss data that have recently arisen that highlight the difficulty in using surface markers to functionally characterize CD8 T-cell populations, and the possibility of using the epigenetic state of cells to more clearly define the functional capacity of CD8 memory T-cell subsets.
Ulrich Z. Hammes, Angus S. Murphy, Claus Schwechheimer
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039875

Abstract:
From embryogenesis to fruit formation, almost every aspect of plant development and differentiation is controlled by the cellular accumulation or depletion of auxin from cells and tissues. The respective auxin maxima and minima are generated by cell-to-cell auxin transport via transporter proteins. Differential auxin accumulation as a result of such transport processes dynamically regulates auxin distribution during differentiation. In this review, we introduce all auxin transporter (families) identified to date and discuss the knowledge on prominent family members, namely, the PIN-FORMED exporters, ATP-binding cassette B (ABCB)-type transporters, and AUX1/LAX importers. We then concentrate on the biochemical features of these transporters and their regulation by posttranslational modifications and interactors.
R. Clay Wright, Britney L. Moss,
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040071

Abstract:
Auxin biology as a field has been at the forefront of advances in delineating the structures, dynamics, and control of plant growth networks. Advances have been enabled by combining the complementary fields of top-down, holistic systems biology and bottom-up, build-to-understand synthetic biology. Continued collaboration between these approaches will facilitate our understanding of and ability to engineer auxin's control of plant growth, development, and physiology. There is a need for the application of similar complementary approaches to improving equity and justice through analysis and redesign of the human systems in which this research is undertaken.
Shanel Tsuda, Matthew E. Pipkin
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a037945

Abstract:
Robust immunity to intracellular infections is mediated by antigen-specific naive CD8 T cells that become activated and differentiate into phenotypically and functionally diverse subsets of effector cells, some of which terminally differentiate and others that give rise to memory cells that provide long-lived protection. This developmental system is an outstanding model with which to elucidate how regulation of chromatin structure and transcriptional control establish gene expression programs that govern cell fate determination, insights from which are likely to be useful for informing the design of immunotherapeutic approaches to engineer durable immunity to infections and tumors. A unifying framework that describes how naive CD8 T cells develop into memory cells is still outstanding. We propose a model that incorporates a common early linear path followed by divergent paths that slowly lose capacity to interconvert and discuss classical and contemporary observations that support these notions, focusing on insights from transcriptional control and chromatin regulation.
Joseph Lipsick
Cold Spring Harbor Perspectives in Biology, Volume 13; https://doi.org/10.1101/cshperspect.a035774

Abstract:
Early studies of transmissible tumors in chickens provided evidence that viruses such as avian leukosis virus (ALV) and Rous sarcoma virus (RSV) can cause cancer in these animals. Doubts about the relevance to human tumors and failures to replicate some early work meant the field of tumor virology followed a bumpy course. Nevertheless, viruses that can cause cancers in rodents and humans were ultimately identified, and several Nobel prizes were awarded for work in this area. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the early history of tumor virus research, from some of the early false starts and debates, to discovery of reverse transcriptase, and identification of human papilloma virus (HPV) as the major cause of cervical cancer.
Yagmur Farsakoglu, Bryan McDonald, Susan M. Kaech
Cold Spring Harbor Perspectives in Biology, Volume 13; https://doi.org/10.1101/cshperspect.a038075

Abstract:
Immunological memory is a hallmark of adaptive immunity that confers long-lasting protection from reinfections. Memory CD8+ T cells provide protection by actively scanning for their cognate antigen and migrating into inflamed tissues. Trafficking patterns of CD8+ T cells are also a major determinant of cell fate outcomes during differentiation into effector and memory cell states. CD8+ T-cell trafficking must therefore be dynamically and tightly regulated to ensure that CD8+ T cells arrive at the correct locations and differentiate to acquire appropriate effector functions. This review aims to discuss the importance of CD8+ T-cell trafficking patterns in regulating effector and memory differentiation, maintenance, and reactivation.
Tasha A. Morrison, William H. Hudson, Danielle A. Chisolm, Yuka Kanno, Han-Yu Shih, Rafi Ahmed, Jorge Henao-Mejia, Markus Hafner, John J. O'Shea
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a037952

Abstract:
Not simply an attribute of the adaptive immune system, immunological memory can be viewed on multiple levels. Accordingly, the molecular basis of memory comprises multiple mechanisms. The advent of new sequencing technologies has greatly enhanced the understanding of gene regulation and lymphocyte specification, and improved measurement of chromatin states affords new insights into the epigenomic and transcriptomic programs that underlie memory. Beyond canonical genes, the involvement of long noncoding RNAs (lncRNAs) is becoming increasingly apparent, and it appears that there are more than two to three times as many lncRNAs as protein-coding genes. lncRNAs can directly interact with DNA, RNA, and proteins, and a single lncRNA can contain multiple modular domains and thus interact with different classes of molecules. Yet, most lncRNAs have not been tested for function, and even fewer knockout mice have been generated. It is therefore timely to consider new potential mechanisms that may contribute to immune memory.
Jaap Rutten, Thea Van Den Berg, Kirsten Ten Tusscher
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040089

Abstract:
Auxin signaling and patterning is an inherently complex process, involving polarized auxin transport, metabolism, and signaling, its effect on developmental zones, as well as growth rates, and the feedback between all these different aspects. This complexity has led to an important role for computational modeling in unraveling the multifactorial roles of auxin in plant developmental and adaptive processes. Here we discuss the basic ingredients of auxin signaling and patterning models for root development as well as a series of key modeling studies in this area. These modeling studies have helped elucidate how plants use auxin signaling to compute the size of their root meristem, the direction in which to grow, and when and where to form lateral roots. Importantly, these models highlight how auxin, through patterning of and collaborating with other factors, can fulfill all these roles simultaneously.
Mikolaj Cieslak, Andrew Owens, Przemyslaw Prusinkiewicz
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040097

Abstract:
Auxin regulates many aspects of plant development and behavior, including the initiation of new outgrowth, patterning of vascular systems, control of branching, and responses to the environment. Computational models have complemented experimental studies of these processes. We review these models from two perspectives. First, we consider cellular and tissue-level models of interaction between auxin and its transporters in shoots. These models form a coherent body of results exploring different hypotheses pertinent to the patterning of new outgrowth and vascular strands. Second, we consider models operating at the level of plant organs and entire plants. We highlight techniques used to reduce the complexity of these models, which provide a path to capturing the essence of studied phenomena while running simulations efficiently.
Nicholas Morffy, Lucia C. Strader
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a039883

Abstract:
Auxin signaling regulates growth and developmental processes in plants. The core of nuclear auxin signaling relies on just three components: TIR1/AFBs, Aux/IAAs, and ARFs. Each component is itself made up of several domains, all of which contribute to the regulation of auxin signaling. Studies of the structural aspects of these three core signaling components have deepened our understanding of auxin signaling dynamics and regulation. In addition to the structured domains of these components, intrinsically disordered regions within the proteins also impact auxin signaling outcomes. New research is beginning to uncover the role intrinsic disorder plays in auxin-regulated degradation and subcellular localization. Structured and intrinsically disordered domains affect auxin perception, protein degradation dynamics, and DNA binding. Taken together, subtle differences within the domains and motifs of each class of auxin signaling component affect signaling outcomes and specificity.
Feiyue Lu,
Cold Spring Harbor Perspectives in Biology; https://doi.org/10.1101/cshperspect.a040949

Abstract:
To predict transcription, one needs a mechanistic understanding of how the numerous required transcription factors (TFs) explore the nuclear space to find their target genes, assemble, cooperate, and compete with one another. Advances in fluorescence microscopy have made it possible to visualize real-time TF dynamics in living cells, leading to two intriguing observations: first, most TFs contact chromatin only transiently; and second, TFs can assemble into clusters through their intrinsically disordered regions. These findings suggest that highly dynamic events and spatially structured nuclear microenvironments might play key roles in transcription regulation that are not yet fully understood. The emerging model is that while some promoters directly convert TF-binding events into on/off cycles of transcription, many others apply complex regulatory layers that ultimately lead to diverse phenotypic outputs. Cracking this kinetic code is an ongoing and challenging task that is made possible by combining innovative imaging approaches with biophysical models.
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