GUMEROV, Vadim and Hedvig HEGYI. MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1]. BIOLOGY DIRECT. LONDON: BIOMED CENTRAL LTD, 2015, vol. 10, October, p. "nestránkováno", 15 pp. ISSN 1745-6150. doi:10.1186/s13062-015-0089-y.
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Basic information
Original name MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1]
Authors GUMEROV, Vadim (643 Russian Federation, belonging to the institution) and Hedvig HEGYI (348 Hungary, guarantor, belonging to the institution).
Other information
Original language English
Type of outcome Article in a journal
Field of Study 10600 1.6 Biological sciences
Country of publisher United Kingdom of Great Britain and Northern Ireland
Confidentiality degree is not subject to a state or trade secret
Impact factor Impact factor: 3.016
RIV identification code RIV/00216224:14740/15:00085548
Organization unit Central European Institute of Technology
UT WoS 000362802800001
Keywords in English Schizophrenia; Methylation; GABBR1; AKT1; MicroRNAs; Gene networks; Protein-protein interactions
Tags OA, rivok
Tags International impact, Reviewed
Changed by Changed by: Martina Prášilová, učo 342282. Changed: 5. 1. 2016 12:24.
Background: While hundreds of genes have been implicated already in the etiology of schizophrenia, the exact cause is not known or the disease is considered multigenic in origin. Recent discoveries of new types of RNAs and the gradual elimination of the "junk DNA" hypothesis refocused the attention on the noncoding part of the human genome. Here we re-analyzed a recent dataset of differentially methylated genes from schizophrenic patients and cross-tabulated them with cis regulatory and repetitive elements and microRNAs known to be involved in schizophrenia. Results: We found that the number of schizophrenia-related (SZ) microRNA targets follows a scale-free distribution with several microRNA hubs and that schizophrenia-related microRNAs with shared targets form a small-world network. The top ten microRNAs with the highest number of SZ gene targets regulate approximately 80 % of all microRNA-regulated genes whereas the top two microRNAs regulate 40-52 % of all such genes. We also found that genes that are regulated by the same microRNAs tend to have more protein-protein interactions than randomly selected schizophrenia genes. This highlights the role microRNAs possibly play in coordinating the abundance of interacting proteins, an important function that has not been sufficiently explored before. The analysis revealed that GABBR1 is regulated by both of the top two microRNAs and acts as a hub by interacting with many schizophrenia-related genes and sharing several types of transcription-binding sites with its interactors. We also found that differentially methylated repetitive elements are significantly more methylated in schizophrenia, pointing out their potential role in the disease. Conclusions: We find that GABBR1 has a central importance in schizophrenia, even if no direct cause and effect have been shown for it for the time. In addition to being a hub in microRNA-derived regulatory pathways and protein-protein interactions, its centrality is also supported by the high number of cis regulatory elements and transcription factor-binding sites that regulate its transcription. These findings are in line with several genome-wide association studies that repeatedly find the major histocompatibility region (where GABBR1 is located) to have the highest number of single nucleotide polymorphisms in schizophrenics. Our model also offers an explanation for the downregulation of protein kinase B, another consistent finding in schizophrenic patients. Our observations support the notion that microRNAs fine-tune the amount of proteins acting in the same biological pathways in schizophrenia, giving further support to the emerging theory of competing endogenous RNAs. Open Peer Review: The manuscript was reviewed by Jaap Heringa, Sandor Pongor and Zoltan Gaspari.
ED1.1.00/02.0068, research and development projectName: CEITEC - central european institute of technology
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