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

Daniel Sasca, Haiyang Yun, George Giotopoulos, Jakub Szybinski, Theo Evan, Nicola K. Wilson, Moritz Gerstung, Paolo Gallipoli, Anthony R. Green, Robert Hills, Nigel Russell, Cameron S. Osborne, Elli Papaemmanuil, Berthold Göttgens, Peter Campbell, Brian J.P. Huntly*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2195-2208
Number of pages14
JournalBlood
Volume134
Issue number24
DOIs
Publication statusPublished - 12 Dec 2019

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