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Abstract
HMGA1 is an abundant non-histone chromatin protein that has been implicated in embryonic development, cancer, and cellular senescence, but its specific role remains elusive. Here, we combine functional genomics approaches with graph theory to investigate how HMGA1 genomic deposition controls high-order chromatin networks in an oncogene-induced senescence model. While the direct role of HMGA1 in gene activation has been described previously, we find little evidence to support this. Instead, we show that the heterogeneous linear distribution of HMGA1 drives a specific 3D chromatin organization. HMGA1-dense loci form highly interactive networks, similar to, but independent of, constitutive heterochromatic loci. This, coupled with the exclusion of HMGA1-poor chromatin regions, leads to coordinated gene regulation through the repositioning of genes. In the absence of HMGA1, the whole process is largely reversed, but many regulatory interactions also emerge, amplifying the inflammatory senescence-associated secretory phenotype. Such HMGA1-mediated fine-tuning of gene expression contributes to the heterogeneous nature of senescence at the single-cell level. A similar ‘buffer’ effect of HMGA1 on inflammatory signalling is also detected in lung cancer cells. Our study reveals a mechanism through which HMGA1 modulates chromatin compartmentalization and gene regulation in senescence and beyond.
HMGA1 helps regulate the topology of the chromatin network, supporting compartmentalization. Here, Olan et al. show that, in oncogene-induced senescence, genes are included or excluded from HMGA1 cores, suggesting HMGA1 has a fine-tuning role.
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1 University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934)
2 University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); The Netherlands Cancer Institute, Division of Tumor Biology and Immunology, The Netherlands Cancer Institute—Oncode In stitute, Amsterdam, The Netherlands (GRID:grid.430814.a) (ISNI:0000 0001 0674 1393)
3 University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Altos Labs Cambridge Institute, Cambridge, UK (GRID:grid.5335.0)
4 The Babraham Institute, Epigenetics Programme, Cambridge, UK (GRID:grid.418195.0) (ISNI:0000 0001 0694 2777)
5 Babraham Research Campus, Nuclear Dynamics Programme, The Babraham Institute, Cambridge, UK (GRID:grid.418195.0) (ISNI:0000 0001 0694 2777); Enhanc3D Genomics Ltd, Cambridge, UK (GRID:grid.418195.0)
6 Kyushu University, Division of Transcriptomics, Medical Institute of Bioregulation, Fukuoka, Japan (GRID:grid.177174.3) (ISNI:0000 0001 2242 4849)
7 Tokyo Institute of Technology, Cell Biology Center, Institute of Innovative Research, Yokohama, Japan (GRID:grid.32197.3e) (ISNI:0000 0001 2179 2105)
8 University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Tokyo Institute of Technology, Tokyo Tech World Research Hub Initiative (WRHI), Institute of Innovative Research, Yokohama, Japan (GRID:grid.32197.3e) (ISNI:0000 0001 2179 2105)