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Chromatin, which consists of DNA and associated proteins, contains genetic information and is a mechanical component of the nucleus. Heterochromatic histone methylation controls nucleus and chromosome stiffness, but the contribution of heterochromatin protein HP1 alpha (CBX5) is unknown. We used a novel HP1 alpha auxin-inducible degron human cell line to rapidly degrade HP1 alpha. Degradation did not alter transcription, local chromatin compaction, or histone methylation, but did decrease chromatin stiffness. Single-nucleus micromanipulation reveals that HP1 alpha is essential to chromatin-based mechanics and maintains nuclear morphology, separate from histone methylation. Further experiments with dimerization-deficient HP1 alpha(I)(165E) indicate that chromatin crosslinking via HP1 alpha dimerization is critical, while polymer simulations demonstrate the importance of chromatin-chromatin crosslinkers in mechanics. In mitotic chromosomes, HP1 alpha similarly bolsters stiffness while aiding in mitotic alignment and faithful segregation. HP1 alpha is therefore a critical chromatin-crosslinking protein that provides mechanical strength to chromosomes and the nucleus throughout the cell cycle and supports cellular functions.
Marko, John F./0000-0003-4151-9530; Biggs, Ronald/0000-0002-9965-6346; Banigan, Edward/0000-0001-5478-7425; Ritland, Joan/0000-0001-5229-0087; Strom, Amy/0000-0002-1674-3242
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Mark Foundation For Cancer Research; Mark Foundation For Cancer Research [AWD1006303]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U01 DA040601, GM114190, U54CA193419, R24DK106766, 1R35GM124820, R01HG009906, U01CA200060, 1UM1HG011536, R00GM123195, U01DA040583]
Strom, Amy R.; Biggs, Ronald J.; Banigan, Edward J.; Wang, Xiaoto; Chiu, Katherine; Herman, Cameron; Collado, Jimena; Yue, Feng; Ritland Politz, Joan C.; and Tait, Leah J., "HP1α is a Chromatin Crosslinker That Controls Nuclear and Mitotic Chromosome Mechanics" (2021). eLife. 657.