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Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10381-10386. doi: 10.1073/pnas.1809480115. Epub 2018 Sep 25.

Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
2
Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.
3
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
4
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu.
5
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037.

Abstract

Nuclear hormone receptors (NRs), such as retinoic acid receptors (RARs), play critical roles in vertebrate development and homeostasis by regulating target gene transcription. Their activity is controlled by ligand-dependent release of corepressors and subsequent recruitment of coactivators, but how these individual receptor modes contribute to development are unknown. Here, we show that mice carrying targeted knockin mutations in the corepressor Silencing Mediator of Retinoid and Thyroid hormone receptor (SMRT) that specifically disable SMRT function in NR signaling (SMRTmRID), display defects in cranial neural crest cell-derived structures and posterior homeotic transformations of axial vertebrae. SMRTmRID embryos show enhanced transcription of RAR targets including Hox loci, resulting in respecification of vertebral identities. Up-regulated histone acetylation and decreased H3K27 methylation are evident in the Hox loci whose somitic expression boundaries are rostrally shifted. Furthermore, enhanced recruitment of super elongation complex is evident in rapidly induced non-Pol II-paused targets in SMRTmRID embryonic stem cells. These results demonstrate that SMRT-dependent repression of RAR is critical to establish and maintain the somitic Hox code and segmental identity during fetal development via epigenetic marking of target loci.

KEYWORDS:

SMRT; homeotic transformation; retinoic acid receptor; somitogenesis; transcriptional repression

PMID:
30254164
PMCID:
PMC6187131
DOI:
10.1073/pnas.1809480115
[Indexed for MEDLINE]
Free PMC Article

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