Distal and proximal cis-regulatory elements sense X-chromosomal dosage and developmental state at theXistlocus

Author:

Gjaltema Rutger A.F.ORCID,Schwämmle Till,Kautz Pauline,Robson Michael,Schöpflin Robert,Lustig Liat Ravid,Brandenburg Lennart,Dunkel Ilona,Vechiatto Carolina,Ntini Evgenia,Mutzel VerenaORCID,Schmiedel Vera,Marsico Annalisa,Mundlos StefanORCID,Schulz Edda G.ORCID

Abstract

AbstractDevelopmental genes such asXist, the master regulator of X-chromosome inactivation (XCI), are controlled by complexcis-regulatory landscapes, which decode multiple signals to establish specific spatio-temporal expression patterns.Xistintegrates information on X-chromosomal dosage and developmental stage to trigger XCI at the primed pluripotent state in females only. Through a pooled CRISPR interference screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements ofXistduring the onset of random XCI. By quantifying how enhancer activity is modulated by X-dosage and differentiation, we find that X-dosage controls the promoter-proximal region in a binary switch-like manner. By contrast, differentiation cues activate a series of distal elements and bring them into closer spatial proximity of theXistpromoter. The strongest distal element is part of an enhancer cluster ∼200 kb upstream of theXistgene which is associated with a previously unannotatedXist-enhancing regulatory transcript, we namedXert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specificXistupregulation at the correct developmental time. Our study is the first step to disentangle how multiple, functionally distinct regulatory regions interact to generate complex expression patterns in mammals.

Publisher

Cold Spring Harbor Laboratory

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