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