2023 APS March Meeting
Volume 68, Number 3
Las Vegas, Nevada (March 5-10)
Virtual (March 20-22); Time Zone: Pacific Time
Session Z06: Genome Organization and Subnuclear Phenomena III: Measuring and Manipulating Genome Organization
11:30 AM–2:30 PM,
Friday, March 10, 2023
Room: Room 129
Sponsoring
Unit:
DBIO
Chair: Siyuan Wang, Princeton University
Abstract: Z06.00001 : Nuclear mechanotransduction & stem cell fate regulation
11:30 AM–12:06 PM
Abstract
Presenter:
Yekaterina Miroshnikova
(NIH)
Author:
Yekaterina Miroshnikova
(NIH)
Precise control of three-dimensional (3-D) nuclear organization is critical for regulation of gene expression and the establishment and maintenance of cell identities. Stem cells execute these identity transitions in dynamic environments where they constantly undergo state changes in response to forces inflicted by cell movements, cell divisions and tissue growth. Recent work from us and others implicate mechanical force, by activating biochemical signaling in the cytoplasm as well as triggering mechanotransduction through nuclear deformation, in remodeling nuclear architecture, chromatin state, and global gene expression patterns in both somatic and embryonic stem cells. Using quantitative imaging and sequencing approaches, we show that mechanical deformation of nuclei results in a stress response characterized by reduced peripheral H3K9me3-marked heterochromatin, attenuated global transcription and increased H3K27me3-mediated silencing of lineage commitment genes. To assess if these changes resulted from a tightly controlled, reversible and stereotypic process or rather represented a stochastic breakdown of homeostasis, we characterized deformation-triggered alterations in chromatin accessibility and transcriptional activity of human induced pluripotent stem cells (hiPS) on a single cell level in their pluripotent state and at exit from pluripotency. Analyses of these data and subsequent follow up experiments revealed a mechano-osmotic nuclear mechanotransduction pathway consisting of two parallel components: 1) an osmotic pathway regulated by nuclear volume loss resulting in global transcriptional repression and a subsequent H3K27me3-regulated mechanical memory that attenuated exit from pluripotency and 2) a nuclear membrane tension-triggered pathway that resulted in activation of mechanoadaptive gene expression driven by mechanosensitive transcription pathways. Collectively this work reveals a universal mechanism by which nuclear deformation triggers changes in chromatin architecture and gene expression, resulting in epigenetic memory affecting stem lineage progression.