Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Identification of ETO2-GLIS2 targets by ChIP-sequencing

ABSTRACT: Acute megakaryoblastic leukemia (AMKL) is a subtype of leukemia primarily diagnosed in childhood and generally associated with poor prognosis. Genetic alterations found in de novo childhood AMKL include the OTT-MAL fusion, MLL and NUP98 fusions and the recently identified ETO2-GLIS2 fusion that involves two transcriptional regulators. In order to identify ETO2-GLIS2-bound regions as well as the chromatin landscape in human AMKL cells, we performed ChIP-seq analyses in AMKL MO7E cell line and in AMKL patient derived cells. Since existing GLIS2 antibodies could not successfully pull-down ETO2-GLIS2, we introduced the GFP at the endogenous GLIS2 loci in the MO7E cell line using a CRISPR/Cas9 approach to obtain physiological expression of a GFP-tagged ETO2-GLIS2 (MO7e-KI cell line). ChIP-seq were performed using antibody against GFP and ETO2 to identify ETO2-GLIS2-bound regions, against ERG to investigate colocalization and against chromatin marks to highlight repressed (H3K27me3) and active (H3K4me3: promoters; H3K27Ac, H3K4me1: enhancers) regions.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas MERCHER

PROVIDER: E-MTAB-4367 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.

Thirant Cécile C Ignacimouttou Cathy C Lopez Cécile K CK Diop M'Boyba M Le Mouël Lou L Thiollier Clarisse C Siret Aurélie A Dessen Phillipe P Aid Zakia Z Rivière Julie J Rameau Philippe P Lefebvre Céline C Khaled Mehdi M Leverger Guy G Ballerini Paola P Petit Arnaud A Raslova Hana H Carmichael Catherine L CL Kile Benjamin T BT Soler Eric E Crispino John D JD Wichmann Christian C Pflumio Françoise F Schwaller Jürg J Vainchenker William W Lobry Camille C Droin Nathalie N Bernard Olivier A OA Malinge Sébastien S Mercher Thomas T

Cancer cell 20170301 3

Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcriptio ...[more]

PMID: 28292442

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Project description:The ETO-family transcriptional corepressors, including ETO, ETO2 and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor – the DBD binds to target genes, while the ETO moiety contributes essentially to its transcriptional property. A direct comparative study of these “homologous” fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in the M2 and M7 subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs (i.e., the Runt domain of AML1 and the zinc finger domain of GLIS2) to bind DNA, they actually share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors such as ETS- and CEBP-family proteins. Functionally, AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as an activator. The repressor-versus-activator functions of AML1-ETO is determined by the abundance of cooperative transcription factors/cofactors on the target genes. Through these mechanisms, AML1-ETO and ETO2-GLIS2 differentially regulate several key transcription factors that are essential for myeloid differentiation. Indeed, AML1-ETO inhibits myeloid differentiation of U937 cells, whereas ETO2-GLIS2 facilitates it. Taken together, this study is the first direct comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context, and the results provide new insights into the context-dependent transcriptional regulatory mechanisms that may underlie how these seemingly “homologous” fusion transcription factors exert distinct functions to drive different subtypes of leukemia.

Dataset Information

Identification of ETO2-GLIS2 targets by ChIP-sequencing

Publications

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.

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