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Gjaltema, R.A.F.* ; Schwämmle, T.* ; Kautz, P.* ; Robson, M.* ; Schöpflin, R.* ; Ravid Lustig, L.* ; Brandenburg, L.O.* ; Dunkel, I.* ; Vechiatto, C.* ; Ntini, E.* ; Mutzel, V.* ; Schmiedel, V.* ; Marsico, A. ; Mundlos, S.* ; Schulz, E.G.*

Distal and proximal cis-regulatory elements sense X chromosome dosage and developmental state at the Xist locus.

Mol. Cell 82, 190-208.e17 (2021)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Grants E:bio Module III-Xnet grant
Wellcome Trust
DFG
Deutsche Forschungsgemeinschaft (DFG)
Human Frontiers Science Program
Max-Planck Research Group Leader program