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

ABSTRACT: 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.

SUBMITTER: Kumar A

PROVIDER: S-EPMC6430136 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Kumar Aditya A Thomas Stephanie K SK Wong Kirsten C KC Lo Sardo Valentina V Cheah Daniel S DS Hou Yang-Hsun YH Placone Jesse K JK Tenerelli Kevin P KP Ferguson William C WC Torkamani Ali A Topol Eric J EJ Baldwin Kristin K KK Engler Adam J AJ

Nature biomedical engineering 20190128 2

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 ...[more]

PMID: 30911429

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Project description:BackgroundGrowing evidences have been revealing that long noncoding RNAs are vital factors in oncogenesis and tumor development. Among them, cancer susceptibility candidate 11 (CASC11) has displayed an impressively essential role in various kinds of cancers including hepatocellular carcinoma (HCC). Nevertheless, its role and potential mechanism in HCC still remain to be fully investigated.MethodsCASC11 expression level was evaluated by real-time polymerase chain reaction, western blotting, and in situ hybridization staining in HCC patients, and its prognostic effect was analyzed. The role of CASC11 in HCC tumorigenesis and progression was investigated by cell proliferation assay, transwell assay, extracellular acidification rate, western blotting, flow cytometry, and an in vivo xenograft model. The interactions among CASC11, E2F transcription factor 1 (E2F1), and eukaryotic translation initiation factor 4A3 (EIF4A3) were explored by using quantitative reverse transcriptase polymerase chain reaction, western blotting, RNA-binding protein immunoprecipitation assay, and chromatin immunoprecipitation assays.ResultsUpregulation of CASC11 was confirmed in HCC tissues and associated with poor prognosis. Loss of function assays showed inhibition of CASC11 expression suppressed HCC cells proliferation, mobility, and glucose metabolism and promoted apoptosis. E2F1 expression significantly decreased after inhibition of CASC11. Rescue experiments illustrated that E2F1 overexpression alleviated the suppression of CASC11 inhibition on HCC progression in vitro and in vivo. Mechanistically, CASC11 recruited EIF4A3 to enhance the stability of E2F1 mRNA. CASC11 and E2F1 impacted the activation of the NF-κB signaling and PI3K/AKT/mTOR pathway and further regulated the expression PD-L1 that is an important target of immunotherapy. In addition, we identified YY1 could modulate CASC11 expression by binding to its promoter.ConclusionsOur data revealed that CASC11 promoted the progression of HCC by means of EIF4A3-mediated E2F1 upregulation, indicating CASC11 is a promising diagnostic biomarker and therapeutic target for HCC.

Project description:UNLABELLED:Next-generation sequencing (NGS) enables the highly sensitive measurement of whole transcriptomes. We report the first application to our knowledge of this technology to the analysis of RNA from a CD4+ T cell line infected with intact HIV. We sequenced the total mRNA from infected cells and detected differences in the expression of both host and viral mRNA. Viral reads represented a large portion of the total mapped sequencing reads: approximately 20% at 12 h postinfection (hpi) and 40% at 24 hpi. We also detected a small but significant suppression of T cell activation-related genes at 12 hpi. This suppression persisted and expanded by 24 hpi, providing new possible markers of virus-induced T cell cytopathology. By 24 hpi, the expression of over 50% of detectable host loci was also altered, indicating widespread alteration of host processes, including RNA processing, splicing, and transport to an extent not previously reported. In addition, next-generation sequencing provided insights into alternative viral RNA splice events and the expression of noncoding RNAs, including microRNA host genes. IMPORTANCE:Recent advances in sequencing technology now allow the measurement of effectively all the RNA in a cell. This approach is especially useful for studying models of virus infection, as it allows the simultaneous measurement of both host and viral RNA. Using next-generation sequencing (NGS), we measured changes in total mRNA from a HIV-infected T cell line. To our knowledge, this is the first application of this technology to the investigation of HIV-host interactions involving intact HIV. We directly measured the amount of viral mRNA in infected cells and detected novel viral RNA splice variants and changes in the host expression of noncoding RNA species. We also detected small changes in T cell activation and other host processes during the early stages of viral replication that increased near the peak of viral replication, providing new candidate biomarkers of T cell death.

Dataset Information

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

Publications

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

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