Abstract
BackgroundPluripotency is characterized by a unique transcriptional state, in which lineage-specification genes are poised for transcription upon exposure to appropriate stimuli, via a bivalency mechanism involving the simultaneous presence of activating and repressive methylation marks at promoter-associated histones. Recent evidence suggests that other mechanisms, such as RNA polymerase II pausing, might be operational in this process, but their regulation remains poorly understood.ResultsHere we identify the non-coding snRNA 7SK as a multifaceted regulator of transcription in embryonic stem cells. We find that 7SK represses a specific cohort of transcriptionally poised genes with bivalent or activating chromatin marks in these cells, suggesting a novel poising mechanism independent of Polycomb activity. Genome-wide analysis shows that 7SK also prevents transcription downstream of polyadenylation sites at several active genes, indicating that 7SK is required for normal transcriptional termination or control of 3′-UTR length. In addition, 7SK suppresses divergent upstream antisense transcription at more than 2,600 loci, including many that encode divergent long non-coding RNAs, a finding that implicates the 7SK snRNA in the control of transcriptional bidirectionality.ConclusionsOur study indicates that a single non-coding RNA, the snRNA 7SK, is a gatekeeper of transcriptional termination and bidirectional transcription in embryonic stem cells and mediates transcriptional poising through a mechanism independent of chromatin bivalency.
Highlights
Pluripotency is characterized by a unique transcriptional state, in which lineage-specification genes are poised for transcription upon exposure to appropriate stimuli, via a bivalency mechanism involving the simultaneous presence of activating and repressive methylation marks at promoter-associated histones
We investigated whether 7SK could mediate transcriptional repression of lineage-specification genes in Embryonic stem cell (ESC) in a naive ground pluripotent state, induced by switching from serum-containing medium to 2i/LIF, a defined medium containing inhibitors of the mitogen activated protein kinase/extracellular regulated kinase (MEK/ERK) and glycogen synthase kinase 3 (GSK3) pathways in combination with leukemia inhibitory factor [8]
Our results suggested that 7SK regulates the expression of lineage-specification genes in ESCs
Summary
Pluripotency is characterized by a unique transcriptional state, in which lineage-specification genes are poised for transcription upon exposure to appropriate stimuli, via a bivalency mechanism involving the simultaneous presence of activating and repressive methylation marks at promoter-associated histones. Recent evidence suggests that other mechanisms, such as RNA polymerase II pausing, might be operational in this process, but their regulation remains poorly understood Pluripotent cells such as embryonic stem cells (ESCs) are able to generate all the cell types of the adult organism, and can acquire different cell fates upon appropriate stimuli. In an induced ground pluripotent state [8], lineage-specification genes exhibit even lower expression and, paradoxically, reduced H3K27me3 [9]. In these conditions increased Pol II pausing is seen at these loci, which may be an alternative mechanism for maintenance of the transcriptional poised state
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