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Nucleic Acids Res. 2018 Apr 20;46(7):3412-3428. doi: 10.1093/nar/gky119.

Combined cistrome and transcriptome analysis of SKI in AML cells identifies SKI as a co-repressor for RUNX1.

Author information

1
Institute of Molecular Biology and Tumor Research (IMT), School of Medicine, Philipps University Marburg, Hans-Meerwein-Str. 2, 35043 Marburg, Germany.
2
Department of Internal Medicine and Hematology, Oncology and Immunology, Philipps University Marburg, University Hospital Giessen and Marburg, Baldingerstr., 35043 Marburg, Germany.
3
Genomics Core Facility, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany.
4
Institute of Molecular Oncology, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany.

Abstract

SKI is a transcriptional co-regulator and overexpressed in various human tumors, for example in acute myeloid leukemia (AML). SKI contributes to the origin and maintenance of the leukemic phenotype. Here, we use ChIP-seq and RNA-seq analysis to identify the epigenetic alterations induced by SKI overexpression in AML cells. We show that approximately two thirds of differentially expressed genes are up-regulated upon SKI deletion, of which >40% harbor SKI binding sites in their proximity, primarily in enhancer regions. Gene ontology analysis reveals that many of the differentially expressed genes are annotated to hematopoietic cell differentiation and inflammatory response, corroborating our finding that SKI contributes to a myeloid differentiation block in HL60 cells. We find that SKI peaks are enriched for RUNX1 consensus motifs, particularly in up-regulated SKI targets upon SKI deletion. RUNX1 ChIP-seq displays that nearly 70% of RUNX1 binding sites overlap with SKI peaks, mainly at enhancer regions. SKI and RUNX1 occupy the same genomic sites and cooperate in gene silencing. Our work demonstrates for the first time the predominant co-repressive function of SKI in AML cells on a genome-wide scale and uncovers the transcription factor RUNX1 as an important mediator of SKI-dependent transcriptional repression.

PMID:
29471413
PMCID:
PMC5909421
DOI:
10.1093/nar/gky119
[Indexed for MEDLINE]
Free PMC Article

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