Modeling by disruption and a selected-for partner for the nude locus
Open Access
- 3 March 2021
- journal article
- research article
- Published by European Molecular Biology Organization in EMBO Reports
- Vol. 22 (3), e49804
- https://doi.org/10.15252/embr.201949804
Abstract
A long-standing problem in biology is how to dissect traits for which no tractable model exists. Here, we screen for genes like the nude locus (Foxn1)-genes central to mammalian hair and thymus development-using animals that never evolved hair, thymi, or Foxn1. Fruit flies are morphologically disrupted by the FOXN1 transcription factor and rescued by weak reductions in fly gene function, revealing molecules that potently synergize with FOXN1 to effect dramatic, chaotic change. Strong synergy/effectivity in flies is expected to reflect strong selection/functionality (purpose) in mammals; the more disruptive a molecular interaction is in alien contexts (flies), the more beneficial it will be in its natural, formative contexts (mammals). The approach identifies Aff4 as the first nude-like locus, as murine AFF4 and FOXN1 cooperatively induce similar cutaneous/thymic phenotypes, similar gene expression programs, and the same step of transcription, pre-initiation complex formation. These AFF4 functions are unexpected, as AFF4 also serves as a scaffold in common transcriptional-elongation complexes. Most likely, the approach works because an interaction's power to disrupt is the inevitable consequence of its selected-for power to benefit.Keywords
Funding Information
- Shiseido Group (Massachusetts General Hospital/Shiseido Co. Ltd. Agreement)
This publication has 102 references indexed in Scilit:
- Genomic approaches towards finding cis-regulatory modules in animalsNature Reviews Genetics, 2012
- HIV-1 Tat and Host AFF4 Recruit Two Transcription Elongation Factors into a Bifunctional Complex for Coordinated Activation of HIV-1 TranscriptionMolecular Cell, 2010
- HIV-1 Tat Assembles a Multifunctional Transcription Elongation Complex and Stably Associates with the 7SK snRNPMolecular Cell, 2010
- Postnatal Tissue-specific Disruption of Transcription Factor FoxN1 Triggers Acute Thymic AtrophyJournal of Biological Chemistry, 2010
- A Higher-Order Complex Containing AF4 and ENL Family Proteins with P-TEFb Facilitates Oncogenic and Physiologic MLL-Dependent TranscriptionCancer Cell, 2010
- AFF4, a Component of the ELL/P-TEFb Elongation Complex and a Shared Subunit of MLL Chimeras, Can Link Transcription Elongation to LeukemiaMolecular Cell, 2010
- Planar Cell Polarity: Keeping Hairs Straight Is Not So SimpleCold Spring Harbor Perspectives in Biology, 2009
- Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitmentThe Journal of Experimental Medicine, 2008
- Delta-like 4 is indispensable in thymic environment specific for T cell developmentThe Journal of Experimental Medicine, 2008
- New member of the winged-helix protein family disrupted in mouse and rat nude mutationsNature, 1994