Cohesin Mutations Induce Chromatin Conformation Perturbation of the H19/IGF2 Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines

Traditionally, Cornelia de Lange Syndrome (CdLS) is considered a cohesinopathy caused by constitutive mutations in cohesin complex genes. Cohesin is a major regulator of chromatin architecture, including the formation of chromatin loops at the imprinted IGF2/H19...

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Autores principales:	Silvana Pileggi, Marta La Vecchia, Elisa Adele Colombo, Laura Fontana, Patrizia Colapietro, Davide Rovina, Annamaria Morotti, Silvia Tabano, Giovanni Porta, Myriam Alcalay, Cristina Gervasini, Monica Miozzo, Silvia Maria Sirchia
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cohesin Cornelia de Lange Syndrome 3D chromatin conformation IGF2/H19 domain WNT pathway imprinted genes Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9be0c72452a44827a476fce44f08dd98
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spelling	oai:doaj.org-article:9be0c72452a44827a476fce44f08dd982021-11-25T16:52:53ZCohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines10.3390/biom111116222218-273Xhttps://doaj.org/article/9be0c72452a44827a476fce44f08dd982021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1622https://doaj.org/toc/2218-273XTraditionally, Cornelia de Lange Syndrome (CdLS) is considered a cohesinopathy caused by constitutive mutations in cohesin complex genes. Cohesin is a major regulator of chromatin architecture, including the formation of chromatin loops at the imprinted <i>IGF2</i>/<i>H19</i> domain. We used 3C analysis on lymphoblastoid cells from CdLS patients carrying mutations in <i>NIPBL</i> and <i>SMC1A</i> genes to explore 3D chromatin structure of the <i>IGF2</i>/<i>H19</i> <i>locus</i> and evaluate the influence of cohesin alterations in chromatin architecture. We also assessed quantitative expression of imprinted <i>loci</i> and WNT pathway genes, together with DMR methylation status of the imprinted genes. A general impairment of chromatin architecture and the emergence of new interactions were found. Moreover, imprinting alterations also involved the expression and methylation levels of imprinted genes, suggesting an association among cohesin genetic defects, chromatin architecture impairment, and imprinting network alteration. The WNT pathway resulted dysregulated: canonical WNT, cell cycle, and WNT signal negative regulation were the most significantly affected subpathways. Among the deregulated pathway nodes, the key node of the frizzled receptors was repressed. Our study provides new evidence that mutations in genes of the cohesin complex have effects on the chromatin architecture and epigenetic stability of genes commonly regulated by high order chromatin structure.Silvana PileggiMarta La VecchiaElisa Adele ColomboLaura FontanaPatrizia ColapietroDavide RovinaAnnamaria MorottiSilvia TabanoGiovanni PortaMyriam AlcalayCristina GervasiniMonica MiozzoSilvia Maria SirchiaMDPI AGarticlecohesinCornelia de Lange Syndrome3D chromatin conformationIGF2/H19 domainWNT pathwayimprinted genesMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1622, p 1622 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cohesin Cornelia de Lange Syndrome 3D chromatin conformation IGF2/H19 domain WNT pathway imprinted genes Microbiology QR1-502
spellingShingle	cohesin Cornelia de Lange Syndrome 3D chromatin conformation IGF2/H19 domain WNT pathway imprinted genes Microbiology QR1-502 Silvana Pileggi Marta La Vecchia Elisa Adele Colombo Laura Fontana Patrizia Colapietro Davide Rovina Annamaria Morotti Silvia Tabano Giovanni Porta Myriam Alcalay Cristina Gervasini Monica Miozzo Silvia Maria Sirchia Cohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines
description	Traditionally, Cornelia de Lange Syndrome (CdLS) is considered a cohesinopathy caused by constitutive mutations in cohesin complex genes. Cohesin is a major regulator of chromatin architecture, including the formation of chromatin loops at the imprinted <i>IGF2</i>/<i>H19</i> domain. We used 3C analysis on lymphoblastoid cells from CdLS patients carrying mutations in <i>NIPBL</i> and <i>SMC1A</i> genes to explore 3D chromatin structure of the <i>IGF2</i>/<i>H19</i> <i>locus</i> and evaluate the influence of cohesin alterations in chromatin architecture. We also assessed quantitative expression of imprinted <i>loci</i> and WNT pathway genes, together with DMR methylation status of the imprinted genes. A general impairment of chromatin architecture and the emergence of new interactions were found. Moreover, imprinting alterations also involved the expression and methylation levels of imprinted genes, suggesting an association among cohesin genetic defects, chromatin architecture impairment, and imprinting network alteration. The WNT pathway resulted dysregulated: canonical WNT, cell cycle, and WNT signal negative regulation were the most significantly affected subpathways. Among the deregulated pathway nodes, the key node of the frizzled receptors was repressed. Our study provides new evidence that mutations in genes of the cohesin complex have effects on the chromatin architecture and epigenetic stability of genes commonly regulated by high order chromatin structure.
format	article
author	Silvana Pileggi Marta La Vecchia Elisa Adele Colombo Laura Fontana Patrizia Colapietro Davide Rovina Annamaria Morotti Silvia Tabano Giovanni Porta Myriam Alcalay Cristina Gervasini Monica Miozzo Silvia Maria Sirchia
author_facet	Silvana Pileggi Marta La Vecchia Elisa Adele Colombo Laura Fontana Patrizia Colapietro Davide Rovina Annamaria Morotti Silvia Tabano Giovanni Porta Myriam Alcalay Cristina Gervasini Monica Miozzo Silvia Maria Sirchia
author_sort	Silvana Pileggi
title	Cohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines
title_short	Cohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines
title_full	Cohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines
title_fullStr	Cohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines
title_full_unstemmed	Cohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines
title_sort	cohesin mutations induce chromatin conformation perturbation of the <i>h19</i>/<i>igf2</i> imprinted region and gene expression dysregulation in cornelia de lange syndrome cell lines
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/9be0c72452a44827a476fce44f08dd98
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Cohesin Mutations Induce Chromatin Conformation Perturbation of the <i>H19</i>/<i>IGF2</i> Imprinted Region and Gene Expression Dysregulation in Cornelia de Lange Syndrome Cell Lines

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