Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-04-24 DOI:10.1016/j.celrep.2025.115633

Jiabei Lian, Yachun An, Wenjing Wei, Yao Lu, Xiyu Zhang, Gongping Sun, Haiyang Guo, Longjin Xu, Xuena Chen, Huili Hu

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Abstract

Liver regeneration is a well-organized and phase-restricted process that involves chromatin remodeling and transcriptional alterations. However, the specific transcription factors (TFs) that act as key "switches" to initiate hepatocyte regeneration and organoid formation remain unclear. Comprehensive integration of RNA sequencing and ATAC sequencing reveals that ATF3 representing "Initiation_on" TF and ONECUT2 representing "Initiation_off" TF transiently modulate the occupancy of target promoters to license liver cells for regeneration. Knockdown of Atf3 or overexpression of Onecut2 not only reduces organoid formation but also delays tissue-damage repair after PHx or CCl₄ treatment. Mechanistically, we demonstrate that ATF3 binds to the promoter of Slc7a5 to activate mTOR signals while the Hmgcs1 promoter loses ONECUT2 binding to facilitate regenerative initiation. The results identify the mechanism for initiating regeneration and reveal the remodeling of transcriptional landscapes and chromatin accessibility, thereby providing potential therapeutic targets for liver diseases with regenerative defects.

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转录景观和染色质可及性揭示了肝脏再生起始和类器官形成的关键调节因子。

肝脏再生是一个组织良好、阶段限制的过程，涉及染色质重塑和转录改变。然而，作为启动肝细胞再生和类器官形成的关键“开关”的特定转录因子（TFs）仍不清楚。RNA测序和ATAC测序的综合整合表明，代表“Initiation_on”TF的ATF3和代表“Initiation_off”TF的ONECUT2可以瞬时调节目标启动子的占用，从而允许肝细胞再生。在PHx或CCl4治疗后，Atf3的下调或Onecut2的过表达不仅会减少类器官的形成，还会延迟组织损伤的修复。在机制上，我们证明了ATF3与Slc7a5的启动子结合以激活mTOR信号，而Hmgcs1启动子失去ONECUT2结合以促进再生启动。结果确定了启动再生的机制，揭示了转录景观和染色质可及性的重塑，从而为具有再生缺陷的肝脏疾病提供了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.