增强子重编程已被提出作为转录调控在肿瘤发生中的关键源头，然而支持这一过程的分子机制尚不清楚。本文中，我们鉴定了一个在乳腺和肺腺癌中异常激活的对于正常发育所必需的增强子簇。删除SRR124-134簇会破坏SOX2致癌基因的表达，引起全基因组转录和染色质可及性的失调，并降低癌细胞在体外形成克隆的能力。原发性肿瘤的分析表明，在乳腺和肺癌患者中，该簇的染色质可及性与SOX2过表达存在相关性。我们证明FOXA1是SRR124-134活性和SOX2转录的激活因子，而NFIB是其抑制因子，揭示了早期发育中涉及的调控机制在癌细胞中的利用。值得注意的是，我们显示在小鼠发育过程中，保守的SRR124和SRR134区域是至关重要的，其纯合缺失导致食管-气管分离的致命失败。这些发现为我们如何在肿瘤发生中重新编程发育增强子提供了见解，并强调了了解发育和疾病过程中的增强子动力学的重要性。© 2023年作者发表。由牛津大学出版社代表核酸研究出版。

Enhancer reprogramming has been proposed as a key source of transcriptional dysregulation during tumorigenesis, but the molecular mechanisms underlying this process remain unclear. Here, we identify an enhancer cluster required for normal development that is aberrantly activated in breast and lung adenocarcinoma. Deletion of the SRR124-134 cluster disrupts expression of the SOX2 oncogene, dysregulates genome-wide transcription and chromatin accessibility and reduces the ability of cancer cells to form colonies in vitro. Analysis of primary tumors reveals a correlation between chromatin accessibility at this cluster and SOX2 overexpression in breast and lung cancer patients. We demonstrate that FOXA1 is an activator and NFIB is a repressor of SRR124-134 activity and SOX2 transcription in cancer cells, revealing a co-opting of the regulatory mechanisms involved in early development. Notably, we show that the conserved SRR124 and SRR134 regions are essential during mouse development, where homozygous deletion results in the lethal failure of esophageal-tracheal separation. These findings provide insights into how developmental enhancers can be reprogrammed during tumorigenesis and underscore the importance of understanding enhancer dynamics during development and disease.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.