Combined cistrome and transcriptome analysis of SKI in AML cells identifies SKI as a co-repressor for RUNX1.
Combined cistrome and transcriptome analysis of SKI in AML cells identifies SKI as a co-repressor for RUNX1.
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DOI：
10.1093/nar/gky119
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发表时间：
2018-04-20
影响因子：
14.9
通讯作者：
Neubauer A
中科院分区：
文献类型：
--
作者：
Feld C;Sahu P;Frech M;Finkernagel F;Nist A;Stiewe T;Bauer UM;Neubauer A
SKI是一种转录共调节因子，在多种人类肿瘤中过表达，例如在急性髓性白血病（AML）中。SKI有助于白血病表型的起源和维持。在这里，我们使用ChIP-seq和RNA-seq分析来鉴定AML细胞中SKI过表达诱导的表观遗传学改变。我们发现，大约三分之二的差异表达基因在SKI缺失后上调，其中>40%在其附近含有SKI结合位点，主要在增强子区域。基因本体分析表明，许多差异表达的基因被注释到造血细胞分化和炎症反应，证实了我们的发现，SKI有助于在HL 60细胞的髓样分化阻滞。我们发现，SKI峰富集RUNX 1的一致性基序，特别是在SKI缺失后上调的SKI靶点。RUNX 1 ChIP-seq显示，近70%的RUNX 1结合位点与SKI峰重叠，主要在增强子区域。SKI和RUNX 1占据相同的基因组位点，并在基因沉默中合作。我们的工作首次证明了SKI在AML细胞中在全基因组范围内的主要共抑制功能，并揭示了转录因子RUNX 1作为SKI依赖性转录抑制的重要介体。
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.
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作者：
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模因套件：用于发现和搜索的工具。
影响因子：
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作者：
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