Department of Hepatobiliary Surgery, School of Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China.
Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300192, China.
Clin Epigenetics. 2024 Nov 5;16(1):154. doi: 10.1186/s13148-024-01769-w.
Assay of Transposase Accessible Chromatin Sequencing (ATAC-seq) is a high-throughput sequencing technique that detects open chromatin regions across the genome. These regions are critical in facilitating transcription factor binding and subsequent gene expression. Herein, we utilized ATAC-seq to identify key molecular targets regulating the development and progression of hepatocellular carcinoma (HCC) and elucidate the underlying mechanisms.
We first compared chromatin accessibility profiles between HCC and normal tissues. Subsequently, RNA-seq data was employed to identify differentially expressed genes (DEGs). Integrating ATAC-seq and RNA-seq data allowed the identification of transcription factors and their putative target genes associated with differentially accessible regions (DARs). Finally, functional experiments were conducted to investigate the effects of the identified regulatory factors and corresponding targets on HCC cell proliferation and migration.
Enrichment analysis of DARs between HCC and adjacent normal tissues revealed distinct signaling pathways and regulatory factors. Upregulated DARs in HCC were enriched in genes related to the MAPK and FoxO signaling pathways and associated with transcription factor families like ETS and AP-1. Conversely, downregulated DARs were associated with the TGF-β, cAMP, and p53 signaling pathways and the CTCF family. Integration of the datasets revealed a positive correlation between specific DARs and DEGs. Notably, PRPF3 emerged as a gene associated with DARs in HCC, and functional assays demonstrated its ability to promote HCC cell proliferation and migration. To the best of our knowledge, this is the first report highlighting the oncogenic role of PRPF3 in HCC. Furthermore, ZNF93 expression positively correlated with PRPF3, and ChIP-seq data indicated its potential role as a transcription factor regulating PRPF3 by binding to its promoter region.
This study provides a comprehensive analysis of the epigenetic landscape in HCC, encompassing both chromatin accessibility and the transcriptome. Our findings reveal that ZNF93 promotes the proliferation and motility of HCC cells through transcriptional regulation of a novel oncogene, PRPF3.
转座酶可及染色质测序（ATAC-seq）是一种高通量测序技术，可检测整个基因组中开放染色质区域。这些区域对于促进转录因子结合和随后的基因表达至关重要。在此，我们利用 ATAC-seq 来鉴定调控肝细胞癌（HCC）发生和发展的关键分子靶标，并阐明其潜在机制。
我们首先比较了 HCC 和正常组织之间的染色质可及性图谱。随后，采用 RNA-seq 数据鉴定差异表达基因（DEGs）。整合 ATAC-seq 和 RNA-seq 数据，鉴定与差异可及区（DAR）相关的转录因子及其潜在靶基因。最后，通过功能实验研究鉴定的调控因子及其相应靶基因对 HCC 细胞增殖和迁移的影响。
对 HCC 和相邻正常组织之间 DAR 的富集分析揭示了不同的信号通路和调控因子。在 HCC 中上调的 DAR 富集于与 MAPK 和 FoxO 信号通路相关的基因，并与 ETS 和 AP-1 等转录因子家族相关。相反，下调的 DAR 与 TGF-β、cAMP 和 p53 信号通路以及 CTCF 家族相关。数据集的整合显示特定 DAR 与 DEGs 之间存在正相关。值得注意的是，PRPF3 是与 HCC 中 DAR 相关的基因，功能测定表明其具有促进 HCC 细胞增殖和迁移的能力。据我们所知，这是首次报道 PRPF3 在 HCC 中的致癌作用。此外，ZNF93 的表达与 PRPF3 呈正相关，ChIP-seq 数据表明其通过结合其启动子区域作为转录因子调节 PRPF3 的潜在作用。
本研究全面分析了 HCC 的表观遗传景观，包括染色质可及性和转录组。我们的研究结果表明，ZNF93 通过转录调控新的癌基因 PRPF3 促进 HCC 细胞的增殖和迁移。
