A cis-regulatory lexicon of DNA motif combinations mediating cell type-specific gene regulation [HiChIP-Seq]. A cis-regulatory lexicon of DNA motif combinations mediating cell type-specific gene regulation [HiChIP-Seq]

Abstract: Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motifs in cis-regulatory elements (CREs), however, the combinations of motifs that mediate cell type-specific gene regulation are undefined. Chromatin accessibility, TF footprinting, and H3K27ac-dependent DNA looping data were generated to identify 7,531 cell type-specific CREs across 15 normal human cell types. A co-enrichment framework nominated 838 cell type-specific, recurrent heterotypic DNA motif combinations (DMCs), which were functionally validated using massively parallel reporter assays. Compared to their normal counterparts, cancer cells induced DMCs linked to neoplasia-enabling processes that operate in normal cells while also engaging entirely new DMCs. These data identify a cis-regulatory combinatorial DNA motif lexicon for cell type-specific gene regulation in diverse normal and diseased human cells. Purpose: To identify a cis-regulatory combinatorial DNA motif lexicon mediating cell type-specific gene regulation in diverse normal and diseased human cells, matched RNA-seq, chromatin accessibility profiling via ATAC-seq, and enhancer-promoter looping via H3K27ac HiChIP was performed in 15 primary human cell types and 6 human cancer cell lines. Processed and raw data for all cell types can be found in this repository. Squamous cell carcinoma cell line raw and processed data can be found at Jung, et al. "XXX". All biological replicates (n=2) are merged. Overall design: 15 primary human cell type and 2 malignant melanoma H3K27ac HiChIP profiles with 2 or 3 biological replicates in vitro NOTE FROMS SUBMITTER: For the melanocytes and keratinocytes raw data, these are primary human samples so we can’t release the raw data files but we can release all processed files.

摘要：基因表达受转录因子（transcription factors, TFs）调控，此类因子可结合顺式调控元件（cis-regulatory elements, CREs）中的同源DNA基序，但目前介导细胞类型特异性基因调控的基序组合仍未明确。本研究生成染色质开放性、TF足迹分析以及依赖H3K27ac的DNA环化相关数据，在15种正常人类细胞类型中鉴定出7531个细胞类型特异性顺式调控元件。通过共富集分析框架，本研究筛选出838个细胞类型特异性、反复出现的异型DNA基序组合（DNA motif combinations, DMCs），并通过大规模平行报告基因实验（massively parallel reporter assays）完成功能验证。与对应正常细胞相比，癌细胞不仅诱导出正常细胞中已存在的、与肿瘤发生相关过程相关的DMCs，还激活了全新的DMCs。本研究的数据为多种正常及病变人类细胞中的细胞类型特异性基因调控提供了一套顺式调控组合DNA基序词典。研究目的：为鉴定介导多种正常及病变人类细胞中细胞类型特异性基因调控的顺式调控组合DNA基序词典，本研究对15种原代人类细胞类型及6种人类癌细胞系开展了配套的RNA测序（RNA-seq）、采用染色质转座酶可及性测序（ATAC-seq）的染色质开放性谱分析，以及通过H3K27ac HiChIP完成的增强子-启动子环化分析。所有细胞类型的处理后数据与原始数据均可在本仓库中获取。鳞状细胞癌细胞系的原始与处理后数据可参见Jung等人发表于《XXX》的研究。所有生物学重复（n=2）均已合并。总体实验设计：包含15种原代人类细胞类型以及2株恶性黑色素瘤的H3K27ac HiChIP谱数据，对应体外实验的生物学重复数为2或3次。提交者备注：黑色素细胞与角质形成细胞的原始数据为原代人类样本，因此无法公开其原始数据文件，但可公开所有处理后的数据文件。