Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations

Background: Lynch syndrome (LS), characterised by an increased risk for cancer, is mainly caused by germline pathogenic variants affecting a mismatch repair gene (MLH1, MSH2, MSH6, PMS2). Occasionally, LS may be caused by constitutional MLH1 epimutation (CME) characterised by soma-wide methylation o...

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Autores: Climent-Cantó, Paula, Subirana-Granés, Marc, Ramos-Rodríguez, Mireia, Dámaso, Estela, Marín, Fátima, Vara, Covadonga, Pérez-González, Beatriz, Raurell Vila, Helena, Munté, Elisabet, Soto, José Luis, Alonso, Ángel, Shin, GiWon, Ji, Hanlee, Hitchins, Megan, Capellá, Gabriel, Pasquali, Lorenzo, Pineda, Marta
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/69656
Acceso en línea:http://hdl.handle.net/10230/69656
http://dx.doi.org/10.1186/s13148-024-01770-3
Access Level:acceso abierto
Palabra clave:Cis-regulatory regions
MLH1 promoter methylation
3D interactions
Chromatin structure
Constitutional MLH1 epimutation
Lynch syndrome
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
title Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
spellingShingle Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
Climent-Cantó, Paula
Cis-regulatory regions
MLH1 promoter methylation
3D interactions
Chromatin structure
Constitutional MLH1 epimutation
Lynch syndrome
title_short Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
title_full Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
title_fullStr Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
title_full_unstemmed Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
title_sort Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations
dc.creator.none.fl_str_mv Climent-Cantó, Paula
Subirana-Granés, Marc
Ramos-Rodríguez, Mireia
Dámaso, Estela
Marín, Fátima
Vara, Covadonga
Pérez-González, Beatriz
Raurell Vila, Helena
Munté, Elisabet
Soto, José Luis
Alonso, Ángel
Shin, GiWon
Ji, Hanlee
Hitchins, Megan
Capellá, Gabriel
Pasquali, Lorenzo
Pineda, Marta
author Climent-Cantó, Paula
author_facet Climent-Cantó, Paula
Subirana-Granés, Marc
Ramos-Rodríguez, Mireia
Dámaso, Estela
Marín, Fátima
Vara, Covadonga
Pérez-González, Beatriz
Raurell Vila, Helena
Munté, Elisabet
Soto, José Luis
Alonso, Ángel
Shin, GiWon
Ji, Hanlee
Hitchins, Megan
Capellá, Gabriel
Pasquali, Lorenzo
Pineda, Marta
author_role author
author2 Subirana-Granés, Marc
Ramos-Rodríguez, Mireia
Dámaso, Estela
Marín, Fátima
Vara, Covadonga
Pérez-González, Beatriz
Raurell Vila, Helena
Munté, Elisabet
Soto, José Luis
Alonso, Ángel
Shin, GiWon
Ji, Hanlee
Hitchins, Megan
Capellá, Gabriel
Pasquali, Lorenzo
Pineda, Marta
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cis-regulatory regions
MLH1 promoter methylation
3D interactions
Chromatin structure
Constitutional MLH1 epimutation
Lynch syndrome
topic Cis-regulatory regions
MLH1 promoter methylation
3D interactions
Chromatin structure
Constitutional MLH1 epimutation
Lynch syndrome
description Background: Lynch syndrome (LS), characterised by an increased risk for cancer, is mainly caused by germline pathogenic variants affecting a mismatch repair gene (MLH1, MSH2, MSH6, PMS2). Occasionally, LS may be caused by constitutional MLH1 epimutation (CME) characterised by soma-wide methylation of one allele of the MLH1 promoter. Most of these are "primary" epimutations, arising de novo without any apparent underlying cis-genetic cause, and are reversible between generations. We aimed to characterise genetic and gene regulatory changes associated with primary CME to elucidate possible underlying molecular mechanisms. Methods: Four carriers of a primary CME and three non-methylated relatives carrying the same genetic haplotype were included. Genetic alterations were sought using linked-read WGS in blood DNA. Transcriptome (RNA-seq), chromatin landscape (ATAC-seq, H3K27ac CUT&Tag) and 3D chromatin interactions (UMI-4C) were studied in lymphoblastoid cell lines. The MLH1 promoter SNP (c.-93G > A, rs1800734) was used as a reporter in heterozygotes to assess allele-specific chromatin conformation states. Results: MLH1 epimutant alleles presented a closed chromatin conformation and decreased levels of H3K27ac, as compared to the unmethylated allele. Moreover, the epimutant MLH1 promoter exhibited differential 3D chromatin contacts, including lost and gained interactions with distal regulatory elements. Of note, rare genetic alterations potentially affecting transcription factor binding sites were found in the promoter-contacting region of CME carriers. Conclusions: Primary CMEs present allele-specific differential interaction patterns with neighbouring genes and regulatory elements. The role of the identified cis-regulatory regions in the molecular mechanism underlying the origin and maintenance of CME requires further investigation.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/69656
http://dx.doi.org/10.1186/s13148-024-01770-3
url http://hdl.handle.net/10230/69656
http://dx.doi.org/10.1186/s13148-024-01770-3
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Clin Epigenetics. 2024 Dec 31;16(1):193
info:eu-repo/grantAgreement/ES/1PE/SAF2015-68016-R
info:eu-repo/grantAgreement/ES/2PE/PID2019-111254RB-I00
info:eu-repo/grantAgreement/ES/2PE/PID2020-117099RB-I00
info:eu-repo/grantAgreement/ES/3PE/PID2023-151585OB-I00
info:eu-repo/grantAgreement/ES/2PE/SAF2017-86242-R
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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spelling Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutationsCliment-Cantó, PaulaSubirana-Granés, MarcRamos-Rodríguez, MireiaDámaso, EstelaMarín, FátimaVara, CovadongaPérez-González, BeatrizRaurell Vila, HelenaMunté, ElisabetSoto, José LuisAlonso, ÁngelShin, GiWonJi, HanleeHitchins, MeganCapellá, GabrielPasquali, LorenzoPineda, MartaCis-regulatory regionsMLH1 promoter methylation3D interactionsChromatin structureConstitutional MLH1 epimutationLynch syndromeBackground: Lynch syndrome (LS), characterised by an increased risk for cancer, is mainly caused by germline pathogenic variants affecting a mismatch repair gene (MLH1, MSH2, MSH6, PMS2). Occasionally, LS may be caused by constitutional MLH1 epimutation (CME) characterised by soma-wide methylation of one allele of the MLH1 promoter. Most of these are "primary" epimutations, arising de novo without any apparent underlying cis-genetic cause, and are reversible between generations. We aimed to characterise genetic and gene regulatory changes associated with primary CME to elucidate possible underlying molecular mechanisms. Methods: Four carriers of a primary CME and three non-methylated relatives carrying the same genetic haplotype were included. Genetic alterations were sought using linked-read WGS in blood DNA. Transcriptome (RNA-seq), chromatin landscape (ATAC-seq, H3K27ac CUT&Tag) and 3D chromatin interactions (UMI-4C) were studied in lymphoblastoid cell lines. The MLH1 promoter SNP (c.-93G > A, rs1800734) was used as a reporter in heterozygotes to assess allele-specific chromatin conformation states. Results: MLH1 epimutant alleles presented a closed chromatin conformation and decreased levels of H3K27ac, as compared to the unmethylated allele. Moreover, the epimutant MLH1 promoter exhibited differential 3D chromatin contacts, including lost and gained interactions with distal regulatory elements. Of note, rare genetic alterations potentially affecting transcription factor binding sites were found in the promoter-contacting region of CME carriers. Conclusions: Primary CMEs present allele-specific differential interaction patterns with neighbouring genes and regulatory elements. The role of the identified cis-regulatory regions in the molecular mechanism underlying the origin and maintenance of CME requires further investigation.This study was supported by the National Institute of Health/National Cancer Institute (R01CA218342), the Spanish Ministry of Science and Innovation, which is part of Agencia Estatal de Investigación (AEI), through the Retos Investigación grants (SAF2015-68016-R, PID2019-111254RB-I00, PID2020-117099RB-I00, PID2023-151585OB-I00, and SAF2017-86242-R), CIBERONC (CB16/12/00234), and the Secretariat for Universities and Research of the Department of Business and Knowledge of the Generalitat de Catalunya grant to support the activities of research groups (2021 SGR 01112). We also thank the CERCA Program/Generalitat de Catalunya for institutional support. M.R.-R. is supported by the IMPULSO Talento Joven grant from DiabetesCERO and the EFSD/Lilly Young Investigator Award.BioMed Central202520252024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/69656http://dx.doi.org/10.1186/s13148-024-01770-3reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésClin Epigenetics. 2024 Dec 31;16(1):193info:eu-repo/grantAgreement/ES/1PE/SAF2015-68016-Rinfo:eu-repo/grantAgreement/ES/2PE/PID2019-111254RB-I00info:eu-repo/grantAgreement/ES/2PE/PID2020-117099RB-I00info:eu-repo/grantAgreement/ES/3PE/PID2023-151585OB-I00info:eu-repo/grantAgreement/ES/2PE/SAF2017-86242-R© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/696562026-05-29T05:05:01Z
score 15.81155

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