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Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis

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...

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Autores principales: Hong, Suk-Hyun, Fang, Sungsoon, Lu, Benson C., Nofsinger, Russell, Kawakami, Yasuhiko, Castro, Glenda L., Yin, Yunqiang, Lin, Chengqi, Yu, Ruth T., Downes, Michael, Izpisúa Belmonte, Juan Carlos, Shilatifard, Ali, Evans, Ronald M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187131/
https://www.ncbi.nlm.nih.gov/pubmed/30254164
http://dx.doi.org/10.1073/pnas.1809480115
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author Hong, Suk-Hyun
Fang, Sungsoon
Lu, Benson C.
Nofsinger, Russell
Kawakami, Yasuhiko
Castro, Glenda L.
Yin, Yunqiang
Lin, Chengqi
Yu, Ruth T.
Downes, Michael
Izpisúa Belmonte, Juan Carlos
Shilatifard, Ali
Evans, Ronald M.
author_facet Hong, Suk-Hyun
Fang, Sungsoon
Lu, Benson C.
Nofsinger, Russell
Kawakami, Yasuhiko
Castro, Glenda L.
Yin, Yunqiang
Lin, Chengqi
Yu, Ruth T.
Downes, Michael
Izpisúa Belmonte, Juan Carlos
Shilatifard, Ali
Evans, Ronald M.
author_sort Hong, Suk-Hyun
collection PubMed
description 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 (SMRT(mRID)), display defects in cranial neural crest cell-derived structures and posterior homeotic transformations of axial vertebrae. SMRT(mRID) 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 SMRT(mRID) 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.
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spelling pubmed-61871312018-10-15 Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis Hong, Suk-Hyun Fang, Sungsoon Lu, Benson C. Nofsinger, Russell Kawakami, Yasuhiko Castro, Glenda L. Yin, Yunqiang Lin, Chengqi Yu, Ruth T. Downes, Michael Izpisúa Belmonte, Juan Carlos Shilatifard, Ali Evans, Ronald M. Proc Natl Acad Sci U S A Biological Sciences 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 (SMRT(mRID)), display defects in cranial neural crest cell-derived structures and posterior homeotic transformations of axial vertebrae. SMRT(mRID) 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 SMRT(mRID) 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. National Academy of Sciences 2018-10-09 2018-09-25 /pmc/articles/PMC6187131/ /pubmed/30254164 http://dx.doi.org/10.1073/pnas.1809480115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Hong, Suk-Hyun
Fang, Sungsoon
Lu, Benson C.
Nofsinger, Russell
Kawakami, Yasuhiko
Castro, Glenda L.
Yin, Yunqiang
Lin, Chengqi
Yu, Ruth T.
Downes, Michael
Izpisúa Belmonte, Juan Carlos
Shilatifard, Ali
Evans, Ronald M.
Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis
title Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis
title_full Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis
title_fullStr Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis
title_full_unstemmed Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis
title_short Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis
title_sort corepressor smrt is required to maintain hox transcriptional memory during somitogenesis
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187131/
https://www.ncbi.nlm.nih.gov/pubmed/30254164
http://dx.doi.org/10.1073/pnas.1809480115
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