Multiple mechanisms regulate H3 acetylation of enhancers in response to thyroid hormone

Autoři: Stine M. Præstholm aff001;  Majken S. Siersbæk aff001;  Ronni Nielsen aff001;  Xuguang Zhu aff002;  Anthony Hollenberg aff003;  Sheue-yann Cheng aff002;  Lars Grøntved aff001;  Anthony N. Hollenberg aff003
Působiště autorů: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark aff001;  Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland, United States of America aff002;  Division of Endocrinology, Diabetes and Metabolism Weill Cornell Medicine, New York, New York, United States of America aff003
Vyšlo v časopise: Multiple mechanisms regulate H3 acetylation of enhancers in response to thyroid hormone. PLoS Genet 16(5): e32767. doi:10.1371/journal.pgen.1008770
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008770


Hormone-dependent activation of enhancers includes histone hyperacetylation and mediator recruitment. Histone hyperacetylation is mostly explained by a bimodal switch model, where histone deacetylases (HDACs) disassociate from chromatin, and histone acetyl transferases (HATs) are recruited. This model builds on decades of research on steroid receptor regulation of transcription. Yet, the general concept of the bimodal switch model has not been rigorously tested genome wide. We have used a genomics approach to study enhancer hyperacetylation by the thyroid hormone receptor (TR), described to operate as a bimodal switch. H3 acetylation, HAT and HDAC ChIP-seq analyses of livers from hypo- and hyperthyroid wildtype, TR deficient and NCOR1 disrupted mice reveal three types of thyroid hormone (T3)-regulated enhancers. One subset of enhancers is bound by HDAC3-NCOR1 in the absence of hormone and constitutively occupy TR and HATs irrespective of T3 levels, suggesting a poised enhancer state in absence of hormone. In presence of T3, HDAC3-NCOR1 dissociates from these enhancers leading to histone hyperacetylation, suggesting a histone acetylation rheostat function of HDACs at poised enhancers. Another subset of enhancers, not occupied by HDACs, is hyperacetylated in a T3-dependent manner, where TR is recruited to chromatin together with HATs. Lastly, a subset of enhancers, is not occupied directly by TR yet requires TR for histone hyperacetylation. This indirect enhancer activation involves co-association with TR bound enhancers within super-enhancers or topological associated domains. Collectively, this demonstrates various mechanisms controlling hormone-dependent transcription and adds significant details to the otherwise simple bimodal switch model.

Klíčová slova:

Gene expression – Gene regulation – Histones – Chromatin – Mammalian genomics – Mouse models – Thyroid hormones – Histone acetylation


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