한빛사논문
Matteo Trovato 1,2, Daria Bunina 1,3, Umut Yildiz 1,2, Nadine Fernandez-Novel Marx 1, Michael Uckelmann 4, Vita Levina4,Yekaterina Perez 5, Ana Janeva 1, Benjamin A. Garcia 5, Chen Davidovich 4, Judith B. Zaugg 3 & Kyung-Min Noh 1,*
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
2Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences, Heidelberg, Germany.
3European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Heidelberg, Germany.
4Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, and EMBL-Australia, Clayton, VIC, Australia.
5Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
*Corresponding author: correspondence to Kyung-Min Noh
Abstract
Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutate histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleash cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to specialized immune cell types. The H3.3K27A mutant disrupts the deposition and spreading of the repressive H3K27me3 mark, particularly impacting bivalent genes with higher basal levels of H3.3 at promoters. Therefore, H3.3K9 and K27 crucially orchestrate repressive chromatin states at cis-regulatory elements and bivalent promoters, respectively, and instruct proper transcription in mESCs.
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