LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cells
Open Access
- 12 December 2016
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 127 (1), 215-229
- https://doi.org/10.1172/jci88016
Abstract
The recognition of β cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain β cell identity. LIM domain–binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic β cells. Inducible ablation of LDB1 in mature β cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted β cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of β cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative β cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain–binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2) — factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of β cells and is a component of active enhancers in both murine and human islets.Keywords
This publication has 83 references indexed in Scilit:
- Structural Basis for LMO2-Driven Recruitment of the SCL:E47bHLH Heterodimer to Hematopoietic-Specific Transcriptional TargetsCell Reports, 2013
- Epigenetics and diabetes treatment: an unrealized promise?Trends in Endocrinology & Metabolism, 2012
- Regulation of chromatin by histone modificationsCell Research, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreasDevelopmental Biology, 2010
- A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programsNature Neuroscience, 2008
- pdx-1 function is specifically required in embryonic β cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasisDevelopmental Biology, 2008
- A Positive Role for NLI/Ldb1 in Long-Range β-Globin Locus Control Region FunctionMolecular Cell, 2007
- LIM-homeodomain proteins Lhx1 and Lhx5, and their cofactor Ldb1, control Purkinje cell differentiation in the developing cerebellumProceedings of the National Academy of Sciences of the United States of America, 2007