2026-04-05T10:39:39Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/2196362025-12-05T12:30:15Zcom_2072_1057col_2072_478798col_2072_478916col_2072_478917
RECERCAT author Climent Cantó, Paula author Subirana Granés, Marc author Ramos-Rodríguez, Mireia author Dámaso, Estela author Marín, Fátima author Vara, Covadonga author Pérez-González, Beatriz author Raurell Vila, Helena author Munté, Elisabet author Soto, José Luis author Alonso, Ángel author Shin, GiWon author Ji, Hanlee author Hitchins, Megan author Capellá, G. (Gabriel) author Pasquali, Lorenzo author Pineda Riu, Marta 2025-03-11T15:49:09Z2025-03-11T15:49:09Z2024-12-312025-03-11T15:49:09Z 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. cc-by (c) Climent-Cantó, P. et al., 2024 http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Epigènesi Adults Càncer colorectal Cromatina Epigenesis Adulthood Colorectal cancer Chromatin Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion