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KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Bertozzi, Tessa M 
Ferguson-Smith, Anne C 

Abstract

Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs in trans in a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance.

Description

Keywords

DNA methylation, KRAB zinc finger proteins, VM-IAP, endogenous retrovirus, metastable epiallele, Animals, Chromatin, Chromosomes, Mammalian, DNA Methylation, Mammals, Mice, Inbred C57BL, Species Specificity, Transcription, Genetic, Zinc Fingers, Zygote

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

117

Publisher

Proceedings of the National Academy of Sciences

Rights

All rights reserved
Sponsorship
Medical Research Council (MR/R009791/1)
Biotechnology and Biological Sciences Research Council (BB/R009996/1)
Wellcome Trust (210757/Z/18/Z)
Biotechnology and Biological Sciences Research Council (BB/G020930/1)