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Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density
Bone mineral density (BMD) is a highly heritable complex trait and is a key indicator for diagnosis and treatment for osteoporosis. In the last decade, numerous susceptibility loci for BMD and fracture have been identified by genome-wide association studies (GWAS); however, fine mapping of these loc...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561425/ https://www.ncbi.nlm.nih.gov/pubmed/34230965 http://dx.doi.org/10.1093/hmg/ddab181 |
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author | Bai, Wei-Yang Xia, Jiang-Wei Rong, Xiao-Li Cong, Pei-Kuan Khederzadeh, Saber Zheng, Hou-Feng |
author_facet | Bai, Wei-Yang Xia, Jiang-Wei Rong, Xiao-Li Cong, Pei-Kuan Khederzadeh, Saber Zheng, Hou-Feng |
author_sort | Bai, Wei-Yang |
collection | PubMed |
description | Bone mineral density (BMD) is a highly heritable complex trait and is a key indicator for diagnosis and treatment for osteoporosis. In the last decade, numerous susceptibility loci for BMD and fracture have been identified by genome-wide association studies (GWAS); however, fine mapping of these loci is challengeable. Here, we proposed a new long-range fine-mapping approach that combined superenhancers (SEs) and microRNAs (miRNAs) data, which were two important factors in control of cell identity and specific differentiation, with the GWAS summary datasets in cell-type-restricted way. Genome-wide SE-based analysis found that the BMD-related variants were significantly enriched in the osteoblast SE regions, indicative of potential long-range effects of such SNPs. With the SNP-mapped SEs (mSEs), 13 accessible long-range mSE-interacted miRNAs (mSE-miRNAs) were identified by integrating osteoblast Hi-C and ATAC-seq data, including three known bone-related miRNAs (miR-132-3p, miR-212-3p and miR-125b-5p). The putative targets of the two newly identified mSE-miRNAs (miR-548aj-3p and miR-190a-3p) were found largely enriched in osteogenic-related pathway and processes, suggesting that these mSE-miRNAs could be functional in the regulation of osteoblast differentiation. Furthermore, we identified 54 genes with the long-range ‘mSE-miRNA’ approach, and 24 of them were previously reported to be related to skeletal development. Besides, enrichment analysis found that these genes were specifically enriched in the post-transcriptional regulation and bone formation processes. This study provided a new insight into the approach of fine-mapping of GWAS loci. A tool was provided for the genome-wide SE-based analysis and the detection of long-range osteoblast-restricted mSE-miRNAs (https://github.com/Zheng-Lab-Westlake/Osteo-Fine-Mapp-SNP2SE2miRNA). |
format | Online Article Text |
id | pubmed-8561425 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-85614252021-11-03 Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density Bai, Wei-Yang Xia, Jiang-Wei Rong, Xiao-Li Cong, Pei-Kuan Khederzadeh, Saber Zheng, Hou-Feng Hum Mol Genet Bioinformatics Article Bone mineral density (BMD) is a highly heritable complex trait and is a key indicator for diagnosis and treatment for osteoporosis. In the last decade, numerous susceptibility loci for BMD and fracture have been identified by genome-wide association studies (GWAS); however, fine mapping of these loci is challengeable. Here, we proposed a new long-range fine-mapping approach that combined superenhancers (SEs) and microRNAs (miRNAs) data, which were two important factors in control of cell identity and specific differentiation, with the GWAS summary datasets in cell-type-restricted way. Genome-wide SE-based analysis found that the BMD-related variants were significantly enriched in the osteoblast SE regions, indicative of potential long-range effects of such SNPs. With the SNP-mapped SEs (mSEs), 13 accessible long-range mSE-interacted miRNAs (mSE-miRNAs) were identified by integrating osteoblast Hi-C and ATAC-seq data, including three known bone-related miRNAs (miR-132-3p, miR-212-3p and miR-125b-5p). The putative targets of the two newly identified mSE-miRNAs (miR-548aj-3p and miR-190a-3p) were found largely enriched in osteogenic-related pathway and processes, suggesting that these mSE-miRNAs could be functional in the regulation of osteoblast differentiation. Furthermore, we identified 54 genes with the long-range ‘mSE-miRNA’ approach, and 24 of them were previously reported to be related to skeletal development. Besides, enrichment analysis found that these genes were specifically enriched in the post-transcriptional regulation and bone formation processes. This study provided a new insight into the approach of fine-mapping of GWAS loci. A tool was provided for the genome-wide SE-based analysis and the detection of long-range osteoblast-restricted mSE-miRNAs (https://github.com/Zheng-Lab-Westlake/Osteo-Fine-Mapp-SNP2SE2miRNA). Oxford University Press 2021-07-06 /pmc/articles/PMC8561425/ /pubmed/34230965 http://dx.doi.org/10.1093/hmg/ddab181 Text en © The Author(s) 2021. Published by Oxford University Press. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Bioinformatics Article Bai, Wei-Yang Xia, Jiang-Wei Rong, Xiao-Li Cong, Pei-Kuan Khederzadeh, Saber Zheng, Hou-Feng Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density |
title | Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density |
title_full | Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density |
title_fullStr | Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density |
title_full_unstemmed | Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density |
title_short | Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density |
title_sort | integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microrna regulatory network for human bone mineral density |
topic | Bioinformatics Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561425/ https://www.ncbi.nlm.nih.gov/pubmed/34230965 http://dx.doi.org/10.1093/hmg/ddab181 |
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