Spatial organizations of heterochromatin underpin nuclear structural integrity of ventricular cardiomyocytes against mechanical stress
Keita Fujiwara,
Tadashi Inoue,
Aya Kimoto,
Jiang Zixian,
Keizo Tokuhiro,
Yoshiki Yasukochi,
Tomoya O. Akama,
Chen-Leng Cai,
Ichiro Shiojima,
Hiroshi Kimura,
Shige H. Yoshimura,
Tomoyuki Nakamura,
Maretoshi Hirai
Affiliations
Keita Fujiwara
Department of Pharmacology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan; Department of Medicine II, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Tadashi Inoue
Department of Pharmacology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Aya Kimoto
School of Life Science and Technology, Institute of Science Tokyo, Yokohama 226-8501, Japan
Jiang Zixian
Laboratory of Plasma Membrane and Nuclear Signaling, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan
Keizo Tokuhiro
Department of Genome Editing, Institute of Biological Sciences, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Yoshiki Yasukochi
Department of Genome Analysis, Institute of Biological Sciences, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Tomoya O. Akama
Department of Pharmacology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Chen-Leng Cai
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangdong 510530, China
Ichiro Shiojima
Department of Medicine II, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Hiroshi Kimura
School of Life Science and Technology, Institute of Science Tokyo, Yokohama 226-8501, Japan; Cell Biology Center, Institute of Integrated Research, Institute of Science Tokyo, Yokohama 226-8503, Japan
Shige H. Yoshimura
Laboratory of Plasma Membrane and Nuclear Signaling, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan
Tomoyuki Nakamura
Department of Pharmacology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Maretoshi Hirai
Department of Pharmacology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan; Corresponding author
Summary: Cardiomyocyte (CM) nuclei are constantly exposed to mechanical stress, but how they maintain their nuclear shape remains unknown. In this study, we found that ventricular CM nuclei acquire characteristic prominent spatial organizations of heterochromatin (SOH), which are disrupted by high-level expression of H2B-mCherry in mice. SOH disruption was associated with nuclear softening, leading to extreme elongation and rupture under unidirectional mechanical stress. Loosened chromatin then leaks into the cytosol, causing severe inflammation and cardiac dysfunction. Although SOH disruption was accompanied by loosened higher-order genomic structures, the change in gene expression before nuclear deformation was mild, suggesting that SOH play major roles in nuclear structural integrity. Aged CM nuclei consistently exhibited scattered SOH and marked elongation. Furthermore, we provide mechanistic insight into the development and maintenance of SOH driven by chromatin compaction and condensate formation. These results highlight SOH as a safeguard of nuclear shape and genomic integrity against mechanical stress.
