Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation.
Animals
B-Lymphocytes
/ metabolism
Cell Cycle Proteins
/ genetics
Cell Lineage
/ genetics
Cell Self Renewal
/ genetics
Chromatin
/ metabolism
Chromatin Immunoprecipitation
Gene Expression Regulation
/ genetics
Gene Knockout Techniques
Hematopoiesis
/ genetics
Hematopoietic Stem Cells
/ cytology
Humans
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myelodysplastic Syndromes
/ genetics
Nuclear Proteins
/ genetics
PAX5 Transcription Factor
/ genetics
RNA-Seq
Synthetic Lethal Mutations
/ genetics
Trans-Activators
/ genetics
Cohesin
Stag1
Stag2
chromatin
hematopoietic stem cells
mouse models
myelodysplasia
nuclear topology
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
07 11 2019
07 11 2019
Historique:
received:
18
09
2018
revised:
19
06
2019
accepted:
09
08
2019
pubmed:
10
9
2019
medline:
10
9
2020
entrez:
10
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31495782
pii: S1934-5909(19)30338-8
doi: 10.1016/j.stem.2019.08.003
pmc: PMC6842438
mid: NIHMS1537710
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
Chromatin
0
EBF1 protein, human
0
Membrane Proteins
0
Nuclear Proteins
0
PAX5 Transcription Factor
0
PAX5 protein, human
0
Pmepa1 protein, mouse
0
STAG1 protein, human
0
STAG2 protein, human
0
Stag2 protein, mouse
0
Trans-Activators
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
682-696.e8Subventions
Organisme : NIH HHS
ID : U54 OD020355
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG003143
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA215317
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197594
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216421
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA143869
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA190861
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA193419
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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