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

Autor: Kumar A; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Thomas SK; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Wong KC; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Lo Sardo V; Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA., Cheah DS; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Hou YH; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Placone JK; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Tenerelli KP; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Ferguson WC; Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA., Torkamani A; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.; Scripps Research Translational Institute, The Scripps Research Institute, La Jolla, CA, USA., Topol EJ; Scripps Research Translational Institute, The Scripps Research Institute, La Jolla, CA, USA.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Baldwin KK; Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA., Engler AJ; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. aengler@ucsd.edu.; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA. aengler@ucsd.edu.
Jazyk: angličtina
Zdroj: Nature biomedical engineering [Nat Biomed Eng] 2019 Feb; Vol. 3 (2), pp. 137-146. Date of Electronic Publication: 2019 Jan 28.
DOI: 10.1038/s41551-018-0344-5
Abstrakt: 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.
Competing Interests: Competing interests The authors declare no competing interests.
Databáze: MEDLINE
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