RT Journal Article
SR Electronic
T1 Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 206367
DO 10.1101/206367
A1 Andrew D. Stephens
A1 Patrick Z. Liu
A1 Edward J. Banigan
A1 Luay M. Almassalha
A1 Vadim Backman
A1 Stephen A. Adam
A1 Robert D. Goldman
A1 John F. Marko
YR 2017
UL http://biorxiv.org/content/early/2017/10/29/206367.abstract
AB 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. Oppositely, 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.