A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression


Autoři: Zachary M. Carico aff001;  Holden C. Stefan aff002;  Megan Justice aff002;  Askar Yimit aff002;  Jill M. Dowen aff001
Působiště autorů: Cancer Epigenetics Training Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff001;  Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff002;  Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff003;  Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff004;  Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff005;  Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff006
Vyšlo v časopise: A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression. PLoS Genet 17(3): e1009435. doi:10.1371/journal.pgen.1009435
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009435

Souhrn

The cohesin complex spatially organizes interphase chromatin by bringing distal genomic loci into close physical proximity, looping out the intervening DNA. Mutation of cohesin complex subunits is observed in cancer and developmental disorders, but the mechanisms through which these mutations may contribute to disease remain poorly understood. Here, we investigate a recurrent missense mutation to the hinge domain of the cohesin subunit SMC1A, observed in acute myeloid leukemia. Engineering this mutation into murine embryonic stem cells caused widespread changes in gene expression, including dysregulation of the pluripotency gene expression program. This mutation reduced cohesin levels at promoters and enhancers, decreased DNA loops and interactions across short genomic distances, and weakened insulation at CTCF-mediated DNA loops. These findings provide insight into how altered cohesin function contributes to disease and identify a requirement for the cohesin hinge domain in three-dimensional chromatin structure.

Klíčová slova:

Cancers and neoplasms – Cloning – Gene expression – Histone modification – Chromatin – Mammalian genomics – Mutation – Yeast


Zdroje

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