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The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9.

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 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.

SUBMITTER: Fisher JB

PROVIDER: S-EPMC5332284 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9.

Fisher J B JB Peterson J J Reimer M M Stelloh C C Pulakanti K K Gerbec Z J ZJ Abel A M AM Strouse J M JM Strouse C C McNulty M M Malarkannan S S Crispino J D JD Milanovich S S Rao S S

Leukemia 20160824 3

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 verifie ...[more]

PMID: 27554164

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Project description:Herpes Simplex Virus 1 (HSV-1) is a human pathogen that has the ability to establish a lifelong infection in the host. During latency, HSV-1 genomes are chromatinized and are abundantly associated with histones in sensory neurons, yet the mechanisms that govern the latent-lytic transition remain unclear. We hypothesize that the latent-lytic switch is controlled by CTCF insulators, positioned within the HSV-1 latent genome. CTCF insulators, together with the cohesin complex, have the ability to establish and maintain chromtin loops that allow distance separated gene regions to be spatially oriented for transcriptional control. In this current study, we demonstrated that the cohesin subunit Rad21 was recruited to latent HSV-1 genomes near four of the CTCF insulators during latency. We showed that the CTCF insulator known as CTRS1/2, positioned downstream from the essential transactivating IE region of ICP4 was only enriched in Rad21 prior to but not during latency, suggesting that the CTRS1/2 insulator is not required for the maintenance of latency. Further, deletion of the CTRL2 insulator, positioned downstream from the LAT enhancer, resulted in a loss of Rad21 enrichment at insulators flanking the ICP4 region at early times post-infection in mice ganglia, suggesting that these insulators are interdependent. Finally, deletion of the CTRL2 insulator resulted in a loss of Rad21 enrichment at the CTRL2 insulator in a cell-type specific manner, and this loss of Rad21 enrichment was correlated to decreased LAT expression, suggesting that Rad21 recruitment to viral genomes is important for efficient gene expression.ImportanceCTCF insulators are important for transcriptional control and increasing evidence suggests that that CTCF insulators, together with the cohesin complex, regulate viral transcription in DNA viruses. The CTCF-cohesin interaction is important for the formation of chromatin loops, structures that orient distance separated elements in close spatial proximity for transcriptional control. Herpes Simplex Virus 1 (HSV-1) has seven putative CTCF insulators that flank the LAT and the IE, indicating that CTCF insulators play a role in the transition from latency to reactivation. Contributions from the work presented here include the finding that CTCF insulators in HSV-1 genomes are differentially enriched in the cohesin subunit Rad21, suggesting that CTCF-cohesin interactions could be establishing and anchoring chromatin loop structures to control viral transcription.

Dataset Information

The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9.

Publications

The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9.

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