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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Oct 9 2018|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank M. Capecchi and M. Petkovich for providing in situ probe constructs of Hox and Cyp26, respectively; J. Rossant and H. Sucov for providing RARE-hsp-lacZ mice; M. L. Privalsky for providing pSG5 GAL4AD-hRARs; A. Atkins for helpful suggestions and critical review of the manuscript; and Lita Ong and Christi Brondos for administrative assistance. Work in the J.C.I.B. laboratory was supported by the G. Harold and Leila Y. Mathers Charitable Foundation and Universidad Católica San Antonio de Murcia (UCAM). R.M.E. is an investigator of the Howard Hughes Medical Institute at the Salk Institute and the March of Dimes Chair in Molecular and Developmental Biology. This work was supported by the Howard Hughes Medical Institute and the National Institutes of Health Grants (DK057978 and HL105278).
© 2018 National Academy of Sciences.All Rights Reserved.