HMGA1 causes a global shift in chromatin architecture linked to transcriptional changes [scRNA-Seq]. HMGA1 causes a global shift in chromatin architecture linked to transcriptional changes [scRNA-Seq]

High Mobility Group A1 (HMGA1) is an architectural chromatin-binding protein that regulates gene expression in various biological contexts, including differentiation and cancer. While previous studies show that HMGA1 acts by binding specific gene promoters or by contributing to the enhanceosome, its global effect on transcription remains unclear. HMGA1 is also critical for the formation of senescence-associated heterochromatic foci (SAHF) in oncogene-induced senescence (OIS), a stable form of cell cycle arrest with a pro-inflammatory phenotype. This link between the two roles of HMGA1, gene regulation and chromatin organisation, has not been fully explained. Here, we used graph theory and data integration from high-throughput assays to investigate how HMGA1 binding impacts the chromatin interactions network. Our results demonstrate that HMGA1 profoundly remodels the global chromatin network during OIS and contributes to stronger compartmentalization. This remodelling goes beyond SAHF, leading to substantial gene repositioning and differential gene expression, highlighting a novel role for HMGA1 in altering chromatin environments. The HMGA1 effects of gene expression go beyond senescence and appear to be relevant in other contexts, such as lung cancer. Overall design: Hi-C, ChIP-seq, RNA-seq and scRNA-seq was performed in IMR90 cells in the Grow and RAS-induced senescence conditions, with and without shHMGA1. ChIP-seq and RNA-seq were also performed in the H1299 cell line.

高迁移率族蛋白A1（High Mobility Group A1, HMGA1）是一类结构性染色质结合蛋白，可在细胞分化、癌症发生等多种生物学情境中调控基因表达。既往研究显示，HMGA1可通过结合特定基因启动子或参与增强体（enhanceosome）的组装发挥调控功能，但其对转录的全局调控效应仍有待阐明。HMGA1在癌基因诱导性衰老（oncogene-induced senescence, OIS）过程中，对衰老相关异染色质焦点（senescence-associated heterochromatic foci, SAHF）的形成至关重要；而OIS是一类伴随促炎表型的稳定细胞周期阻滞状态。HMGA1的基因调控与染色质组织这两项功能之间的内在关联，目前尚未得到充分阐释。本研究借助图论分析与高通量实验数据整合手段，探究了HMGA1结合对染色质相互作用网络的调控机制。研究结果表明，HMGA1可在OIS过程中显著重塑全局染色质互作网络，并增强染色质区室化程度。该重塑效应并非仅局限于SAHF的形成，还会引发大规模的基因位置重排与差异基因表达，揭示了HMGA1通过重塑染色质微环境发挥功能的全新作用途径。HMGA1对基因表达的调控作用并不限于细胞衰老过程，在肺癌等其他生物学场景中同样具有重要意义。本研究的实验设计如下：在处于增殖状态与RAS诱导性衰老状态的IMR90细胞中，分别设置敲低HMGA1（shHMGA1）与阴性对照组，开展Hi-C、ChIP-seq、RNA-seq及scRNA-seq实验；同时在H1299细胞系中开展ChIP-seq与RNA-seq实验。