Single-Cell Sequencing of Mouse Thymocytes Reveals Mutational Landscape Shaped by Replication Errors, Mismatch Repair, and H3K36me3

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Aska , E-M , Dermadi , D & Kauppi , L 2020 , ' Single-Cell Sequencing of Mouse Thymocytes Reveals Mutational Landscape Shaped by Replication Errors, Mismatch Repair, and H3K36me3 ' , iScience , vol. 23 , no. 9 , 101452 . https://doi.org/10.1016/j.isci.2020.101452

Title: Single-Cell Sequencing of Mouse Thymocytes Reveals Mutational Landscape Shaped by Replication Errors, Mismatch Repair, and H3K36me3
Author: Aska, Elli-Mari; Dermadi, Denis; Kauppi, Liisa
Contributor: University of Helsinki, Research Program in Systems Oncology
University of Helsinki, Department of Biochemistry and Developmental Biology
University of Helsinki, Medicum
Date: 2020-09-25
Language: eng
Number of pages: 25
Belongs to series: iScience
ISSN: 2589-0042
URI: http://hdl.handle.net/10138/321119
Abstract: DNA mismatch repair (MMR) corrects replication errors and is recruited by the histone mark H3K36me3, enriched in exons of transcriptionally active genes. To dissect in vivo the mutational landscape shaped by these processes, we employed single-cell exome sequencing on T cells of wild-type andMMR-deficient (Mlh1(-/-)) mice. Within active genes, we uncovered a spatial bias in MMR efficiency: 3' exons, often H3K36me3-enriched, acquire significantly fewer MMR-dependent mutations compared with 5' exons. Huwe1 and Mcm7 genes, both active during lymphocyte development, stood out as mutational hotspots in MMR-deficient cells, demonstrating their intrinsic vulnerability to replication error in this cell type. Both genes are H3K36me3-enriched, which can explain MMR-mediated elimination of replication errors in wild-type cells. Thus, H3K36me3 can boost MMR in transcriptionally active regions, both locally and globally. This offers an attractive concept of thriftyMMR targeting, where critical genes in each cell type enjoy preferential shielding against de novo mutations.
Subject: READ ALIGNMENT
DNA
MECHANISMS
MLH1
RNA
INSTABILITY
GENERATION
SIGNATURES
DEFICIENT
ELEMENTS
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
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