Cohesin members STAG1 and STAG2 display distinct roles in chromatin accessibility and topological control of HSC self-renewal and differentiation Journal Article
| Authors: | Viny, A. D.; Bowman, R. L.; Liu, Y.; Lavallée, V. P.; Eisman, S. E.; Xiao, W.; Durham, B. H.; Navitski, A.; Park, J.; Braunstein, S.; Alija, B.; Karzai, A.; Csete, I. S.; Witkin, M.; Azizi, E.; Baslan, T.; Ott, C. J.; Pe'er, D.; Dekker, J.; Koche, R.; Levine, R. L. |
| Article Title: | Cohesin members STAG1 and STAG2 display distinct roles in chromatin accessibility and topological control of HSC self-renewal and differentiation |
| Abstract: | Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation. © 2019 Elsevier Inc. In murine hematopoietic Stag2 deletion, Stag1 rescues topologically associated domains in the absence of Stag2 but cannot restore the chromatin architecture required for hematopoietic lineage commitment. PU.1 target genes lose accessibility and expression. Induced target gene expression, but not PU.1 overexpression, is sufficient to restore differentiation in the altered chromatin state. © 2019 Elsevier Inc. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; gene deletion; nonhuman; comparative study; cohesin; animal cell; mouse; animal tissue; cell function; sister chromatid; gene expression; animal experiment; cohort analysis; gene locus; transcription factor; cell differentiation; epigenetics; chromatin; chromatin immunoprecipitation; genomic instability; hematopoietic stem cells; binding site; hematopoiesis; hematopoietic stem cell; mouse models; chromosome segregation; chromatin structure; rna sequence; myelodysplasia; human; priority journal; article; stem cell self-renewal; stag2; nuclear topology; stag1; cohesin subunit stag1; cohesin subunit stag2 |
| Journal Title: | Cell Stem Cell |
| Volume: | 25 |
| Issue: | 5 |
| ISSN: | 1934-5909 |
| Publisher: | Cell Press |
| Date Published: | 2019-11-07 |
| Start Page: | 682 |
| End Page: | 696.e8 |
| Language: | English |
| DOI: | 10.1016/j.stem.2019.08.003 |
| PUBMED: | 31495782 |
| PROVIDER: | scopus |
| PMCID: | PMC6842438 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 December 2019 -- Source: Scopus |
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