Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies.
Biomarkers, Tumor
Cell Cycle Proteins
/ genetics
Cell Line, Tumor
Chromosomal Proteins, Non-Histone
/ genetics
Female
Gene Dosage
Gene Expression Regulation, Leukemic
Hematopoietic Stem Cells
/ metabolism
Histones
/ metabolism
Humans
Male
Mutation
Myeloproliferative Disorders
/ diagnosis
Neoplasm Grading
Protein Binding
Proto-Oncogene Proteins c-ets
/ metabolism
Regulatory Sequences, Nucleic Acid
Repressor Proteins
/ metabolism
Cohesins
ETS Translocation Variant 6 Protein
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
12 12 2019
12 12 2019
Historique:
received:
10
05
2019
accepted:
04
09
2019
pubmed:
14
9
2019
medline:
31
3
2020
entrez:
14
9
2019
Statut:
ppublish
Résumé
Cohesin complex disruption alters gene expression, and cohesin mutations are common in myeloid neoplasia, suggesting a critical role in hematopoiesis. Here, we explore cohesin dynamics and regulation of hematopoietic stem cell homeostasis and differentiation. Cohesin binding increases at active regulatory elements only during erythroid differentiation. Prior binding of the repressive Ets transcription factor Etv6 predicts cohesin binding at these elements and Etv6 interacts with cohesin at chromatin. Depletion of cohesin severely impairs erythroid differentiation, particularly at Etv6-prebound loci, but augments self-renewal programs. Together with corroborative findings in acute myeloid leukemia and myelodysplastic syndrome patient samples, these data suggest cohesin-mediated alleviation of Etv6 repression is required for dynamic expression at critical erythroid genes during differentiation and how this may be perturbed in myeloid malignancies.
Identifiants
pubmed: 31515253
pii: S0006-4971(20)73150-2
doi: 10.1182/blood.2019001553
pmc: PMC7484777
doi:
Substances chimiques
Biomarkers, Tumor
0
Cell Cycle Proteins
0
Chromosomal Proteins, Non-Histone
0
Histones
0
Proto-Oncogene Proteins c-ets
0
Repressor Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2195-2208Subventions
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R009708/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18680/A25508
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 by The American Society of Hematology.
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