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| Status |
Public on Oct 19, 2017 |
| Title |
Control of microRNA expression by mitochondrial function |
| Platform organisms |
Homo sapiens; Mus musculus; Rattus norvegicus; Human alphaherpesvirus 1; Human betaherpesvirus 5; human gammaherpesvirus 4; JC polyomavirus; Human immunodeficiency virus 1; Human gammaherpesvirus 8; Betapolyomavirus hominis; Betapolyomavirus macacae |
| Sample organism |
Homo sapiens |
| Experiment type |
Non-coding RNA profiling by array
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| Summary |
Normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Interruption of this mechanism has been implicated in the dysregulation of many cancer-related pathways, including cell death programs and tumor suppressor networks. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted a miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line. mtDNA restoration reversed this miRNA to parental levels, suggesting that it is an epigenetically-regulated mediator of retrograde signaling. We further demonstrated by methylation specific PCR and bisulfite sequencing that miR-663 is epigenetically regulated by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of rotenone-suppressed miR-663 expression by N-acetylcysteine suggested that mitochondrial dysfunction–induced reactive oxygen species play a role in epigenetic miR-663 regulation. We noted that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits, e.g. NDUFB8, SDHB, UQCRFS1, and COX4L1. miR-663 also regulated the OXPHOS assembly factors NDUFAF1, SDHAF2, UQCC2, and SCO1 and was required for respiratory supercomplex stability. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The miR-663 sponge reduced OXPHOS complex activity and increased in vitro cellular proliferation and promoted tumor development in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide first evidence for miRNA mediating retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis.
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| Overall design |
RNA from four cell lines was used in this array: A 143B parental cell line, a Rho0 cell line in which mitochondrial DNA was depleted and two cybrid cell lines in which platelets were fused with the Rho0 lines. One RNA sample per treatment group was used.
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| Contributor(s) |
Carden T, Singh K |
| Citation(s) |
29066618 |
| Submission date |
Sep 26, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Keshav Singh |
| E-mail(s) |
kksingh@uab.edu
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| Organization name |
University of Alabama at Birmingham
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| Department |
Genetics
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| Street address |
720 20th Street South Kaul 630
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| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35294 |
| Country |
USA |
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| Platforms (1) |
| GPL7724 |
miRCURY LNA microRNA Array, v. 9.2, all organisms |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA412221 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE104277_RAW.tar |
5.7 Mb |
(http)(custom) |
TAR (of TXT, XLSX) |
| GSE104277_annotated_matrix.txt.gz |
5.0 Kb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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