Mechanical activation of noncoding-RNA-mediated regulation of disease-associated phenotypes in human cardiomyocytes

Autor: Eric J. Topol, Yang-Hsun Hou, Aditya Kumar, Stephanie Thomas, Valentina Lo Sardo, Kevin Tenerelli, Kirsten C. Wong, Jesse K. Placone, Ali Torkamani, William C. Ferguson, Adam J. Engler, Kristin K. Baldwin, Daniel S Cheah
Rok vydání: 2019
Předmět:
Zdroj: Nature biomedical engineering, vol 3, iss 2
ISSN: 2157-846X
DOI: 10.1038/s41551-018-0344-5
Popis: How common polymorphisms in noncoding genome regions can regulate cellular function remains largely unknown. Here we show that cardiac fibrosis, mimicked using a hydrogel with controllable stiffness, affects the regulation of the phenotypes of human cardiomyocytes by a portion of the long noncoding RNA ANRIL, the gene of which is located in the disease-associated 9p21 locus. In a physiological environment, cultured cardiomyocytes derived from induced pluripotent stem cells obtained from patients who are homozygous for cardiovascular-risk alleles (R/R cardiomyocytes) or from healthy individuals who are homozygous for nonrisk alleles contracted synchronously, independently of genotype. After hydrogel stiffening to mimic fibrosis, only the R/R cardiomyocytes exhibited asynchronous contractions. These effects were associated with increased expression of the short ANRIL isoform in R/R cardiomyocytes, which induced a c-Jun N-terminal kinase (JNK) phosphorylation-based mechanism that impaired gap junctions (particularly, loss of connexin-43 expression) following stiffening. Deletion of the risk locus or treatment with a JNK antagonist was sufficient to maintain gap junctions and prevent asynchronous contraction of cardiomyocytes. Our findings suggest that mechanical changes in the microenvironment of cardiomyocytes can activate the regulation of their function by noncoding loci.
Databáze: OpenAIRE
Externí odkaz: