López Camila, Barnon Mohammad T, Beacon Tasnim H, Nardocci Gino, Davie James R
CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
Gene. 2022 Jun 5;826:146463. doi: 10.1016/j.gene.2022.146463. Epub 2022 Mar 28.
Epigenetic processes are radically altered in cancer cells. The altered epigenetic events may include histone post-translational modifications (PTMs), DNA modifications, and/or alterations in the levels and modifications of chromatin modifying enzymes and chromatin remodelers. With changes in gene programming are changes in the genomic distribution of histone PTMs. Genes that are poised or transcriptionally active have histone H3 trimethylated lysine 4 (H3K4me3) located at the transcription start site and at the 5' end of the gene. However, a small population of genes that are involved in cell identity or cancer cell properties have a broad H3K4me3 domain that may stretch for several kilobases through the coding region of the gene. Each cancer cell type appears to mark a select set of cancer-related genes in this manner. In this study, we determined which genes were differentially marked with the broad H3K4me3 domain in normal-like (MCF10A), luminal-type breast cancer (MCF7), and triple-negative breast cancer (MDA-MB-231) cells. We also determined whether histone H3 acetylated lysine 4 (H3K4ac), also a mark of active promoters, had a broad domain configuration. We applied two peak callers (MACS2, PeakRanger) to analyze H3K4me3 and H3K4ac chromatin immunoprecipitation sequencing (ChIP-Seq) data. We identified genes with a broad H3K4me3 and/or H3K4ac domain specific to each cell line and show that the genes have critical roles in the breast cancer subtypes. Furthermore, we show that H3K4ac marks enhancers. The identified genes with the broad H3K4me3/H3K4ac domain have been targeted in clinical and pre-clinical studies including therapeutic treatments of breast cancer.
表观遗传过程在癌细胞中发生了根本性改变。这些改变的表观遗传事件可能包括组蛋白翻译后修饰（PTMs）、DNA修饰，和/或染色质修饰酶及染色质重塑因子水平与修饰的改变。随着基因编程的变化，组蛋白PTMs的基因组分布也会改变。处于准备状态或转录活跃的基因，其组蛋白H3赖氨酸4三甲基化（H3K4me3）位于转录起始位点和基因的5'端。然而，一小部分参与细胞特性或癌细胞特性的基因具有广泛的H3K4me3结构域，该结构域可能通过基因的编码区域延伸数千个碱基对。每种癌细胞类型似乎都以这种方式标记一组特定的癌症相关基因。在本研究中，我们确定了在类正常（MCF10A）、管腔型乳腺癌（MCF7）和三阴性乳腺癌（MDA-MB-231）细胞中，哪些基因被广泛的H3K4me3结构域差异标记。我们还确定了同样作为活跃启动子标记的组蛋白H3赖氨酸4乙酰化（H3K4ac）是否具有广泛的结构域构型。我们应用两种峰检测工具（MACS2、PeakRanger）来分析H3K4me3和H3K4ac染色质免疫沉淀测序（ChIP-Seq）数据。我们鉴定出了每种细胞系特有的具有广泛H3K4me3和/或H3K4ac结构域的基因，并表明这些基因在乳腺癌亚型中起关键作用。此外，我们表明H3K4ac标记增强子。已在临床和临床前研究（包括乳腺癌治疗）中靶向了具有广泛H3K4me3/H3K4ac结构域的鉴定基因。
