The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of HoxA7 and HoxA9

Joseph B. Fisher; Jonathan Peterson; Michael Reimer; Cary Stelloh; Kirthi Pulakanti; Zachary J. Gerbec; Alex M. Abel; Jennifer Miksanek Strouse; Christopher Strouse; Maureen McNulty; Subramaniam Malarkannan; John D. Crispino; Samuel Milanovich; Sridhar Rao

doi:10.1038/leu.2016.240

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The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of HoxA7 and HoxA9

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The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of HoxA7 and HoxA9

Joseph B. Fisher, Jonathan Peterson, Michael Reimer, Cary Stelloh, Kirthi Pulakanti, Zachary J. Gerbec, Alex M. Abel, Jennifer Miksanek Strouse, Christopher Strouse, Maureen McNulty, …

Leukemia, Vol.31(3), pp.712-719

08/24/2016

DOI: 10.1038/leu.2016.240

PMCID: PMC5332284

PMID: 27554164

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https://www.ncbi.nlm.nih.gov/pmc/articles/5332284View

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Abstract

Acute myelogenous leukemia (AML) is a high-risk hematopoietic malignancy caused by a variety of mutations, including genes encoding the cohesin complex. Recent studies have demonstrated that reduction in cohesin complex levels leads to enhanced self-renewal in hematopoietic stem and progenitors (HSPCs). We sought to delineate the molecular mechanisms by which cohesin mutations promote enhanced HSPC self-renewal since this represents a critical initial step during leukemic transformation. We verified that RNAi against the cohesin subunit Rad21 causes enhanced self-renewal of HSPCs in vitro through derepression of Polycomb Repressive Complex 2 (PRC2) target genes, including Hoxa7 and Hoxa9 . Importantly, knockdown of either Hoxa7 or Hoxa9 suppressed self-renewal, implying both are critical downstream effectors of reduced cohesin levels. We further demonstrate that the cohesin and PRC2 complexes interact and are bound in close proximity to Hoxa7 and Hoxa9. Rad21 depletion resulted in decreased levels of H3K27me3 at the Hoxa7 and Hoxa9 promoters, consistent with Rad21 being critical to proper gene silencing by recruiting the PRC2 complex. Our data demonstrates that the cohesin complex regulates PRC2 targeting to silence Hoxa7 and Hoxa9 and negatively regulate self-renewal. Our studies identify a novel epigenetic mechanism underlying leukemogenesis in AML patients with cohesin mutations.

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Title: Subtitle: The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of HoxA7 and HoxA9
Creators: Joseph B. Fisher - Versiti Blood Center of Wisconsin
Jonathan Peterson - Versiti Blood Center of Wisconsin
Michael Reimer - Versiti Blood Center of Wisconsin
Cary Stelloh - Versiti Blood Center of Wisconsin
Kirthi Pulakanti - Versiti Blood Center of Wisconsin
Zachary J. Gerbec - Medical College of Wisconsin
Alex M. Abel - Medical College of Wisconsin
Jennifer Miksanek Strouse - Medical College of Wisconsin
Christopher Strouse - Medical College of Wisconsin
Maureen McNulty - Northwestern University
Subramaniam Malarkannan - Versiti Blood Center of Wisconsin
John D. Crispino - Northwestern University
Samuel Milanovich - University of South Dakota
Sridhar Rao - Versiti Blood Center of Wisconsin
Resource Type: Journal article
Publication Details: Leukemia, Vol.31(3), pp.712-719
DOI: 10.1038/leu.2016.240
PMID: 27554164
PMCID: PMC5332284
NLM abbreviation: Leukemia
ISSN: 0887-6924
eISSN: 1476-5551
Language: English
Date published: 08/24/2016
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984360051102771

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