Biology subjects

Chronis, K.

Publications and source records attributed to Chronis, K..

3 recordsLinked to original sources

bioRxiv2025

A Single Mutation in TRPC6 Protects Mice from Acute Lung Injury by Regenerating Endothelium

Regenerating vascular endothelium under sepsis, trauma, and viral infections is vital for promoting the resolution of inflammatory diseases such as acute lung injury (ALI). Transient receptor potential canonical (TRPC) channels mediated Ca2+ entry compromises organ functions and survival from lung injury. Through decoding the domain in TRPC6 responsible for vascular injury, we unveiled the intricate molecular mechanisms underlying vascular regeneration in injured tissue. We found that the substitution of isoleucine111 within the Ist ankyrin domain of TRPC6 for its isomer 111leucine (I111L-TRPC6) altered channel localization at the membrane, blocked TRPC6-mediated Ca2+ entry and cation currents without affecting TRPC6 protein expression. Next, we delivered WT-TRPC6 and I111L-TRPC6 to the endothelial cells (ECs) of TRPC6 knockout mice using liposomes and found that while WT-TRPC6 induced lung vascular inflammatory injury and EC death these responses were blocked in lungs expressing I111L-TRPC6 mutant. Instead, the I111L-TRPC6 mutant promoted lung EC proliferation and prevented vascular injury. These responses were recapitulated in a preclinical mouse model of ALI after injection of engineered TRPC6-blocking peptide, suggesting a novel strategy for regenerating anti-inflammatory vascular niche and preventing ALI therapeutically.

cell biology↗

bioRxiv2020

An Xist-dependent protein assembly mediates Xist localization and gene silencing

Nuclear compartments play diverse roles in regulating gene expression, yet the molecular forces and components driving compartment formation are not well understood. Studying how the lncRNA Xist establishes the inactive-X-chromosome (Xi)-compartment, we found that the Xist RNA-binding-proteins PTBP1, MATR3, TDP43, and CELF1 form a condensate to create an Xi-domain that can be sustained in the absence of Xist. The E-repeat-sequence of Xist serves a multivalent binding-platform for these proteins. Without the E-repeat, Xist initially coats the X-chromosome during XCI onset but subsequently disperses across the nucleus with loss of gene silencing. Recruitment of PTBP1, MATR3, TDP-43 or CELF1 to {Delta}E-Xist rescues these phenotypes, and requires both self-association of MATR3 and TDP-43 and a heterotypic PTBP1-MATR3-interaction. Together, our data reveal that Xist sequesters itself within the Xi-territory and perpetuates gene silencing by seeding a protein-condensate. Our findings uncover an unanticipated mechanism for epigenetic memory and elucidate the interplay between RNA and RNA-binding-proteins in creating compartments for gene regulation.

molecular biology↗

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗