The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9. Leukemia 2017 Mar;31(3):712-719
Date
08/25/2016Pubmed ID
27554164Pubmed Central ID
PMC5332284DOI
10.1038/leu.2016.240Scopus ID
2-s2.0-84989244308 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
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 as 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 that 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.
Author List
Fisher JB, Peterson J, Reimer M, Stelloh C, Pulakanti K, Gerbec ZJ, Abel AM, Strouse JM, Strouse C, McNulty M, Malarkannan S, Crispino JD, Milanovich S, Rao SAuthors
Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of WisconsinSridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AneuploidyAnimals
Cell Cycle Proteins
Cell Proliferation
Cell Self Renewal
Chromosomal Proteins, Non-Histone
Cluster Analysis
DNA-Binding Proteins
Epigenetic Repression
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation
Hematopoietic Stem Cells
Histones
Homeodomain Proteins
Mice
Models, Biological
Multigene Family
Multiprotein Complexes
Myeloid Cells
Neoplasm Proteins
Nuclear Proteins
Phosphoproteins
Protein Binding
Protein Interaction Domains and Motifs
