HMGA1 orchestrates chromatin compartmentalization and sequesters genes into 3D networks coordinating senescence heterogeneity

Year: 2024

Type: article

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.

Source: Nature Communications

DOI: 10.1038/s41467-024-51153-8

Authors: Ioana Olan, Masami Ando-Kuri, Aled J. Parry, Tetsuya Handa, Stefan Schoenfelder, Peter Fraser, Yasuyuki Ohkawa, Hiroshi Kimura, Masako Narita, Masashi Narita

Institutions: University of Cambridge, Cancer Research UK, The Netherlands Cancer Institute, Babraham Institute, Kyushu University, Medical Institute of Bioregulation, Kyushu University, Tokyo Institute of Technology, Cell Biology Center, Cancer Research UK Cambridge Center

Language: English

Topic: Genomics and Chromatin Dynamics

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,790

Funders: Japan Agency for Medical Research and Development, Babraham Institute, UK Research and Innovation, Cancer Research UK, Diabetes UK, Ministry of Education, Culture, Sports, Science and Technology, BIRAX, Medical Research Council, Biotechnology and Biological Sciences Research Council, Japan Society for the Promotion of Science, Research Institute for Information Technology, Kyushu University, Cancer Research UK Cambridge Institute, University of Cambridge

OpenAlex ID: W4401517070