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Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease ph...

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Autores principales: Schierding, William, Horsfield, Julia A, O'Sullivan, Justin M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327319/
https://www.ncbi.nlm.nih.gov/pubmed/32917770
http://dx.doi.org/10.1136/jmedgenet-2020-107095
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author Schierding, William
Horsfield, Julia A
O'Sullivan, Justin M
author_facet Schierding, William
Horsfield, Julia A
O'Sullivan, Justin M
author_sort Schierding, William
collection PubMed
description Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested. Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed). Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function. Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.
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spelling pubmed-83273192021-08-19 Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways Schierding, William Horsfield, Julia A O'Sullivan, Justin M J Med Genet Functional Genomics Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested. Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed). Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function. Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders. BMJ Publishing Group 2021-08 2020-09-11 /pmc/articles/PMC8327319/ /pubmed/32917770 http://dx.doi.org/10.1136/jmedgenet-2020-107095 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Functional Genomics
Schierding, William
Horsfield, Julia A
O'Sullivan, Justin M
Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
title Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
title_full Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
title_fullStr Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
title_full_unstemmed Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
title_short Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
title_sort low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
topic Functional Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327319/
https://www.ncbi.nlm.nih.gov/pubmed/32917770
http://dx.doi.org/10.1136/jmedgenet-2020-107095
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AT osullivanjustinm lowtolerancefortranscriptionalvariationatcohesingenesisaccompaniedbyfunctionallinkstodiseaserelevantpathways