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Genome Res. 2014 Jun;24(6):942-53. doi: 10.1101/gr.169029.113. Epub 2014 May 2.

Natural variation of histone modification and its impact on gene expression in the rat genome.

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Max-Delbrück-Center for Molecular Medicine (MDC), 13125 Berlin, Germany;
Max-Delbrück-Center for Molecular Medicine (MDC), 13125 Berlin, Germany; Department of Computational Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany;
National Heart and Lung Institute, Cardiovascular Genetics and Genomics, London, SW3 6NP, United Kingdom; Duke-NUS Graduate Medical School, 169857 Singapore; National Heart Center Singapore, 169609 Singapore;
Center for Molecular Medicine, University Medical Center Utrecht, Hubrecht Institute KNAW, 3584 CT Utrecht, The Netherlands;
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, NL-9713 AV Groningen, The Netherlands;
Groningen Bioinformatics Centre (GBIC), Groningen Biomolecular Sciences and Biotechnology Institute (GBB), 9747AG Groningen, The Netherlands;
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), iBiTec-S, Université Paris-Sud, CNRS FRE3377, F-91191 Gif-sur-Yvette cedex, France;
Institut of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, CZ-14220 Prague 4, Czech Republic;
Department of Computational Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany;
Max-Delbrück-Center for Molecular Medicine (MDC), 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Berlin, 13125 Berlin, Germany.


Histone modifications are epigenetic marks that play fundamental roles in many biological processes including the control of chromatin-mediated regulation of gene expression. Little is known about interindividual variability of histone modification levels across the genome and to what extent they are influenced by genetic variation. We annotated the rat genome with histone modification maps, identified differences in histone trimethyl-lysine levels among strains, and described their underlying genetic basis at the genome-wide scale using ChIP-seq in heart and liver tissues in a panel of rat recombinant inbred and their progenitor strains. We identified extensive variation of histone methylation levels among individuals and mapped hundreds of underlying cis- and trans-acting loci throughout the genome that regulate histone methylation levels in an allele-specific manner. Interestingly, most histone methylation level variation was trans-linked and the most prominent QTL identified influenced H3K4me3 levels at 899 putative promoters throughout the genome in the heart. Cis- acting variation was enriched in binding sites of distinct transcription factors in heart and liver. The integrated analysis of DNA variation together with histone methylation and gene expression levels showed that histoneQTLs are an important predictor of gene expression and that a joint analysis significantly enhanced the prediction of gene expression traits (eQTLs). Our data suggest that genetic variation has a widespread impact on histone trimethylation marks that may help to uncover novel genotype-phenotype relationships.

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