Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells

Trombly, Daniel J.; Whitfield, Troy W.; Padmanabhan, Srivatsan; Gordon, Jonathan A. R.; Lian, Jane B.; Wijnen, André J. van; Zaidi, Sayyed K.; Stein, Janet L.

doi:10.1186/s12864-015-1445-0

Cited by 33 publications

(56 citation statements)

References 64 publications

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“…In Kasumi cells both HAT (p300) and co-repressor activities (NCoR,[143]; HDAC1 and 2, Figure S21) were associated with F12/5′ RH and NRAMP1 3′ CTCF stretch, implying dynamic regulation that is corroborated in ME-1 cells, wherein RNA Pol II, TBP, p300 and HDAC also bind these elements. In addition, both F6 and F10-F3 bound p300 and HDAC in ME-1 and Kasumi cells, implying early mobilization of these elements downstream of CD34 + HSPC.…”

Section: Resultsmentioning

confidence: 90%

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Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs). Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor (CTCF) sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer (S-E) key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3′ inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3′ CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors (TFs) include CCAAT enhancer binding protein beta (C/EBPb), purine rich DNA binding protein (PU.1), early growth response 2 (EGR2) and signal transducer and activator of transcription 1 (STAT1) while hypoxia-inducible factors (HIFs) and interferon regulatory factor 1 (IRF1) may stimulate iron acquisition in pro-inflammatory conditions. Mouse orthologous locus is generally conserved; chromatin patterns typify a de novo myelo-monocytic gene whose expression is tightly controlled by TFs Pu.1, C/ebps and Irf8; Irf3 and nuclear factor NF-kappa-B p 65 subunit (RelA) regulate expression in inflammatory conditions. Functional differences in the determinants identified at these orthologous loci imply that species-specific mechanisms control gene expression.

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Section: Resultsmentioning

confidence: 90%

“…NRAMP1 epigenetic profile in different AML models [139,141,142,143,144] may therefore inform on TF spatiotemporal contribution to regulate NRAMP1 expression.…”

Section: Resultsmentioning

confidence: 99%

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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“…Several translocations and mutations at the RUNX1 gene locus are associated with leukemia [14–17]. However, the regulatory activity of RUNX1 is not confined to the hematopoietic lineage.…”

Section: Introductionmentioning

confidence: 99%

RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells

Barutcu

Hong²,

Lajoie

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. This suggests an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells.

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“…Indeed, multiple studies demonstrate that, although wildtype RUNX1 and RUNX1-RUNX1T1 both bind the majority of target genes, each protein also uniquely regulates the expression of a subset of genes Ben-Ami et al 2013;Shimada et al 2000;Gardini et al 2008;Ptasinska et al 2012Ptasinska et al , 2014Li et al 2016;Trombly et al 2015). In addition, knockdown of RUNX1 in Kasumi-1 cells causes decreased expression of genes known to regulate the mitotic checkpoint implying that requirement for wildtype RUNX1 is rooted in its ability to transactivate critical cell cycle progression genes (Ben-Ami et al 2013).…”

Section: T(8;21) Amlmentioning

confidence: 96%

RUNX1 and CBFβ Mutations and Activities of Their Wild-Type Alleles in AML

Hyde

Liu

Friedman

2017

Advances in Experimental Medicine and Biology

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Mutations in RUNX1 and CBFB have long been recognized as important in hematological malignancies. Point mutations and deletions of RUNX1 are frequently found in myelodysplastic syndrome, myeloproliferative disease, and acute myeloid leukemia. Germline mutations in RUNX1 are associated with familial platelet disorder with predisposition to AML. In addition, as will be discussed in other chapters, both RUNX1 and CBFB are involved in recurrent chromosomal rearrangements in leukemia. More recently, roles for the non-mutated RUNX1 and CBFB genes have been identified in multiple leukemia subtypes. This chapter will discuss the roles of RUNX1 and CBFB, both in diseases caused by their mutations or deletions, as well as in the context of chromosomal rearrangements.

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Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells

Cited by 33 publications

References 64 publications

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells

RUNX1 and CBFβ Mutations and Activities of Their Wild-Type Alleles in AML

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