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Distal and proximal cis-regulatory elements sense X chromosome dosage and developmental state at the Xist locus.
Mol. Cell 82, 190-208.e17 (2021)
Developmental genes such as Xist, which initiates X chromosome inactivation, are controlled by complex cis-regulatory landscapes, which decode multiple signals to establish specific spatiotemporal expression patterns. Xist integrates information on X chromosome dosage and developmental stage to trigger X inactivation in the epiblast specifically in female embryos. Through a pooled CRISPR screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements of Xist at the onset of random X inactivation. Chromatin profiling reveals that X-dosage controls the promoter-proximal region, while differentiation cues activate several distal enhancers. The strongest distal element lies in an enhancer cluster associated with a previously unannotated Xist-enhancing regulatory transcript, which we named Xert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specific Xist upregulation at the correct developmental time. With this study, we start to disentangle how multiple, functionally distinct regulatory elements interact to generate complex expression patterns in mammals.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Crispr Screens ; Crispri ; X-chromosome Inactivation ; Xert ; Xist ; Chromatin Modifications ; Enhancers ; Epigenetics ; Lncrna; Gene-expression; Read Alignment; Noncoding Rna; Transcription Factors; Inactivation Center; Reveals Principles; Tsix Transcription; Human Genome; In-vitro; Chromatin
ISSN (print) / ISBN
1097-2765
e-ISSN
1097-4164
Journal
Molecular Cell
Quellenangaben
Volume: 82,
Issue: 1,
Pages: 190-208.e17
Publisher
Elsevier
Publishing Place
50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)
Grants
E:bio Module III-Xnet grant
Wellcome Trust
DFG
Deutsche Forschungsgemeinschaft (DFG)
Human Frontiers Science Program
Max-Planck Research Group Leader program
Wellcome Trust
DFG
Deutsche Forschungsgemeinschaft (DFG)
Human Frontiers Science Program
Max-Planck Research Group Leader program