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

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.

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Publication Details

Journal
Nature Communications
Published
2024-08-12
DOI
https://doi.org/10.1038/s41467-024-51153-8
Citations
20
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
4.68

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

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20 citations
Nature Communications
Genomics and Chromatin Dynamics
4.68
article

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

Tetsuya Handa, Hiroshi Kimurâ, Ioana Olan, Aled Parry, Masami Ando‐Kuri, Peter Fraser, Yasuyuki Ohkawa, Masashi Narita, Stefan Schoenfelder, Masako Narita
article en
20 citations

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.

Nature CommunicationsVol. 15(1)
Tokyo Institute of Technology (JP), Babraham Institute (GB), Kyushu University (JP), University of Cambridge (GB), Cancer Research UK (GB), Cancer Research UK Cambridge Center (GB), Granta Design (United Kingdom) (GB), Oncode Institute (NL), Innovative Research (United States) (US), Genomics England (GB), Genomics (United Kingdom) (GB)
Japan Agency for Medical Research and Development, 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
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Openalex Percentile: Top 4%
Genomics and Chromatin Dynamics
4.68
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