Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation

Cell Stem Cell. 2019 Nov 7;25(5):682-696.e8. doi: 10.1016/j.stem.2019.08.003. Epub 2019 Sep 5.


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.

Keywords: Cohesin; Stag1; Stag2; chromatin; hematopoietic stem cells; mouse models; myelodysplasia; nuclear topology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Lineage / genetics
  • Cell Self Renewal / genetics*
  • Chromatin / metabolism*
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation / genetics
  • Gene Knockout Techniques
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • PAX5 Transcription Factor / genetics
  • PAX5 Transcription Factor / metabolism
  • RNA-Seq
  • Synthetic Lethal Mutations / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism


  • Cell Cycle Proteins
  • Chromatin
  • EBF1 protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • PAX5 Transcription Factor
  • PAX5 protein, human
  • Pmepa1 protein, mouse
  • STAG1 protein, human
  • STAG2 protein, human
  • Stag2 protein, mouse
  • Trans-Activators