title: Rapid activation of the bivalent gene Sox21 requires displacement of multiple layers of gene-silencing machinery.
abstract: The rapid formation of numerous tissues during development is highly dependent on the swift activation of key developmental regulators. Recent studies indicate that many key regulatory genes are repressed in embryonic stem cells (ESCs), yet poised for rapid activation due to the presence of both activating (H3K4 trimethylation) and repressive (H3K27 trimethylation) histone modifications (bivalent genes). However, little is known about bivalent gene regulation. In this study, we investigated the regulation of the bivalent gene Sox21, which is activated rapidly when ESCs differentiate in response to increases in Sox2. Chromatin immunoprecipitation demonstrated that prior to differentiation, the Sox21 gene is bound by a complex array of repressive and activating transcriptional machinery. Upon activation, all identified repressive machinery and histone modifications associated with the gene are lost, but the activating modifications and transcriptional machinery are retained. Notably, these changes do not occur when ESCs differentiate in response to retinoic acid. Moreover, ESCs lacking a functional PRC2 complex fail to activate this gene, apparently due to its association with other repressive complexes. Together, these findings suggest that bivalent genes, such as Sox21, are silenced by a complex set of redundant repressive machinery, which exit rapidly in response to appropriate differentiation signals.
authors.affiliation: Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Chakravarthy
authors.forename: Briana D
authors.initials: BD
authors.lastname: Ormsbee
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Mallanna
authors.forename: Angie
authors.initials: A
authors.lastname: Rizzino
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055749:SOXB2 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D046912:Multiprotein Complexes; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; D055749:SOXB2 Transcription Factors; C527783:Sox2 protein, mouse; C484489:Sox21 protein, mouse; D014212:Tretinoin