Abstract
Maintenance of stem cell plasticity is determined by the ability to balance opposing forces that control gene expression. Regulation of transcriptional networks, signaling cues and chromatin-modifying mechanisms constitute crucial determinants of tissue equilibrium. Histone modifications can affect chromatin compaction, therefore co-transcriptional events that influence their deposition determine the propensities toward quiescence, self-renewal, or cell specification. The Paf1 complex (Paf1C) is a critical regulator of RNA PolII elongation that controls gene expression and deposition of histone modifications, however few studies have focused on its role affecting stem cell fate decisions. Here we delineate the functions of Paf1C in pluripotency and characterize its impact in deposition of H2B ubiquitylation (H2BK120-ub) and H3K79 methylation (H3K79me), 2 fundamental histone marks that shape transcriptional regulation. We identify that H2BK120-ub is increased in the absence of Paf1C on its embryonic stem cell targets, in sharp contrast to H3K79me, suggesting opposite functions in the maintenance of self-renewal. Furthermore, we found that core pluripotency genes are characterized by a dual gain of H2BK120-ub and loss of H3K79me on their gene bodies. Our findings elucidate molecular mechanisms of cellular adaptation and reveal novel functions of Paf1C in the regulation of the self-renewal network.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2315-2322 |
| Number of pages | 8 |
| Journal | Cell Cycle |
| Volume | 16 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 17 2017 |
Funding
A.S. has been supported by the New York State Stem Cell Program (NYSTEM) of the New York State Health Department (Institutional NYU Stem Cell Training Grant C026880). I.A. is supported by the National Institutes of Health (RO1CA133379, RO1CA105129, RO1CA149655, 5RO1CA173636, 1RO1CA194923) and the NYSTEM program (NYSTEM-N11G-255). A. Heguy and the NYU Genome Technology Center is supported in part by the National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P30CA016087–30. P.N. is supported by the National Cancer Institute (R00CA188293–02), the American Society of Hematology, the Zell Foundation, the St. Baldrick's Foundation, the Leukemia Research Foundation and the Chicago Region Physical Science-Oncology Center (CR-PSOC). We thank all members of the Aifantis laboratory for useful comments and discussions. We thank A. Heguy and the NYU Genome Technology Center for expertise with sequencing experiments. This work has used computing resources at the High Performance Computing Facility at the NYU Medical Center.
Keywords
- Elongation
- Embryonic stem cells
- Paf1 complex
- Phf5a
- Pluripotency
- Promoter-proximal pausing
- RNA Polymerase II
- Self-renewal network
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
- Developmental Biology