Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins
Year: 2017
Type: article
Abstract: Nuclear shape and architecture influence gene localization, mechanotransduction, transcription, and cell function. Abnormal nuclear morphology and protrusions termed "blebs" are diagnostic markers for many human afflictions including heart disease, aging, progeria, and cancer. Nuclear blebs are associated with both lamin and chromatin alterations. A number of prior studies suggest that lamins dictate nuclear morphology, but the contributions of altered chromatin compaction remain unclear. We show that chromatin histone modification state dictates nuclear rigidity, and modulating it is sufficient to both induce and suppress nuclear blebs. Treatment of mammalian cells with histone deacetylase inhibitors to increase euchromatin or histone methyltransferase inhibitors to decrease heterochromatin results in a softer nucleus and nuclear blebbing, without perturbing lamins. Conversely, treatment with histone demethylase inhibitors increases heterochromatin and chromatin nuclear rigidity, which results in reduced nuclear blebbing in lamin B1 null nuclei. Notably, increased heterochromatin also rescues nuclear morphology in a model cell line for the accelerated aging disease Hutchinson-Gilford progeria syndrome caused by mutant lamin A, as well as cells from patients with the disease. Thus, chromatin histone modification state is a major determinant of nuclear blebbing and morphology via its contribution to nuclear rigidity.
Source: Molecular Biology of the Cell
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, American Heart Association, Chicago Community Trust, LUNGevity Foundation, Chicago Biomedical Consortium, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Division of Materials Research, Division of Chemical, Bioengineering, Environmental, and Transport Systems
Awards: G1099719253, Statistical mechanics of DNA-protein interactions and chromosome organization, Analysis of lamin-chromatin interactions and their regulation of chromosome organization and gene expression, Micromechanical Analysis of Chromosome Structure, G290908823, Spatio-Temporal Organization of Chromatin and Information Transfer in Cancer, Center for 3D Structure and Physics of the Genome, Risk-stratification of Prostate Cancers via Field Carcinogenesis Nanocytology, G5269227014, EFRI-BioFlex: Miniature, low-cost fiber-optics technology for measurement of tissue structure at sub-diffractional length scales: a platform for cancer screening, G7195742200, Dissecting chromatin and lamin contributions to nuclear structure and function, Optical Nanoscale Analysis of Buccal Cells: Transforming Lung Cancer Screening, G9000124324, G9000158695, Activities of nucleoprotein complexes visualized in single-molecule experiments
OpenAlex ID: W2765510117