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Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies.

Accepted version
Peer-reviewed

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Authors

Sasca, Daniel 
Yun, Haiyang 
Giotopoulos, George  ORCID logo  https://orcid.org/0000-0003-1390-6592
Szybinski, Jakub 
Evan, Theo 

Abstract

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.

Description

Keywords

Biomarkers, Tumor, Cell Cycle Proteins, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Female, Gene Dosage, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Histones, Humans, Male, Mutation, Myeloproliferative Disorders, Neoplasm Grading, Protein Binding, Proto-Oncogene Proteins c-ets, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Cohesins, ETS Translocation Variant 6 Protein

Journal Title

Blood

Conference Name

Journal ISSN

0006-4971
1528-0020

Volume Title

134

Publisher

American Society of Hematology

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/R009708/1)
European Research Council (647685)
Wellcome Trust (109967/Z/15/Z)