Affiliation:
1. Centre for Cellular and Molecular Biology 1 , Hyderabad 500007 , India
2. Institute for Stem Cell Science and Regenerative Medicine 2 , Bangalore 560065 , India
3. National Center for Biological Sciences 3 , Bangalore 560065 , India
Abstract
ABSTRACT
Adult stem cells persist in mammalian tissues by entering a state of reversible quiescence, referred to as G0, which is associated with low levels of transcription. Using cultured myoblasts and muscle stem cells, we report that in G0, global RNA content and synthesis are substantially repressed, correlating with decreased RNA polymerase II (RNAPII) expression and activation. Integrating RNAPII occupancy and transcriptome profiling, we identify repressed networks and a role for promoter-proximal RNAPII pausing in G0. Strikingly, RNAPII shows enhanced pausing in G0 on repressed genes encoding regulators of RNA biogenesis (such as Ncl, Rps24, Ctdp1), and release of pausing is associated with increased expression of these genes in G1. Knockdown of these transcripts in proliferating cells leads to induction of G0 markers, confirming the importance of their repression in establishment of G0. A targeted screen of RNAPII regulators revealed that knockdown of Aff4 (a positive regulator of elongation) unexpectedly enhances expression of G0-stalled genes and hastens S phase; however, the negative elongation factor (NELF) complex, a regulator of pausing, appears to be dispensable. We propose that RNAPII pausing contributes to transcriptional control of a subset of G0-repressed genes to maintain quiescence and impacts the timing of the G0-G1 transition.
This article has an associated First Person interview with the first authors of the paper.
Funder
Council of Scientific and Industrial Research, India
Department of Biotechnology, Ministry of Science and Technology, India
Department of Atomic Energy, Government of India
National Centre for Biological Sciences
Publisher
The Company of Biologists
Cited by
6 articles.
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