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

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.

Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia

“…SKI was also found to be overexpressed in AML and proposed to repress retinoic acid receptor and RUNX1mediated signaling. [53][54][55] . In addition, SKI was reported to control HSC fitness in myelodysplastic syndromes (MDS) 56 .…”

The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC

“…We conclude that the increased expression of MICA and ULBP2 in PaTu8988t cells upon SKI knockdown may contribute to a better NK cell-mediated killing but SKI seems to suppress susceptibility against NK cell-mediated killing also by additional, not yet defined mechanisms. In this regard, we found in acute myeloid leukemia (AML) cells that SKI acts rather as a transcriptional repressor and inhibits target genes associated with inflammatory response, immune cell differentiation as well as TNFα signaling via NFκB [ 28 ]. Hence, SKI-expressing tumor cells may evade NK cell-killing via inhibition of pro-inflammatory factors like TNFα.…”

“…Human siGENOME SKI siRNA SMARTpool (M-003927-02-0005) and non-targeting siRNA #5 (D-001210-05) were purchased from Horizon Discovery (Waterbach, UK). ChIP-seq data were collected [ 28 ] and bioinformatical analysis are described there in the Materials & Methods section.…”

Genomics-Guided Immunotherapy for Precision Medicine in Cancer

“…30 A recent study, which utilized gene expression from TCGA and transcription factor binding data from Cistrome, found that transcription factors SKI and RUNX1 occupy the same genomic sites to silence gene expression in acute myeloid leukemia. 31 This demonstrates the potential of publicly available NGS data to expand ones understanding of regulatory mechanisms in cancer.…”