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在结直肠癌发生的早期，启动子-增强子连接的全局丧失和基因表达的重新平衡。

Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.

机构信息

Department of Genetics, Stanford School of Medicine, Stanford, CA, USA.

Ultima Genomics, Newark, CA, USA.

出版信息

Nat Cancer. 2024 Nov;5(11):1697-1712. doi: 10.1038/s43018-024-00823-z. Epub 2024 Oct 30.

DOI:10.1038/s43018-024-00823-z
PMID:39478119
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11584406/
Abstract

Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.

摘要

尽管三维（3D）基因组结构对基因调控至关重要，但它在疾病中的作用仍不明确。我们通过对 33 个结肠样本进行高分辨率染色质构象图谱分析，这些样本来自家族性腺瘤性息肉病（FAP）患者不同早期肿瘤生长阶段，追踪了结直肠癌（CRC）的进化和恶性转化。我们的分析揭示了在早期恶性阶段，全基因组顺式调控连接性的大量进行性丧失，与非线性基因调控效应相关。在未受影响的黏膜中，具有高启动子增强子（P-E）连接性的基因与基础表达水平的升高无关，但在晚期阶段往往会上调。与正常结肠上皮细胞相比，抑制高连接性启动子可优先抑制 CRC 细胞中的基因表达。我们的结果表明存在两阶段模型，其中肿瘤转化将 P-E 连接性从冗余状态降低到转录水平的限速状态，突出了 3D 基因组结构和早期 CRC 进展过程中基因调控之间的复杂相互作用。

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