Genetic control of chromatin in a Human population. O. Delaneau1, S. Waszak2, A. Gschwind3, H. Kilpinen1, S. Raghav2, R. Witwicki3, A. Orioli3, M. Wiederkehr3, M. Gutierrez-Arcelus1, N. Panousis1, A. Yurovsky1, T. Lappalainen1, L. Romano-Palumbo1, A. Planchon1, D. Bielser1, I. Padioleau1, G. Udin2, S. Thurnheer4, D. Hacker4, N. Hernandez3, A. Reymond3, B. Deplancke2, E. Dermitzakis1 1) Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; 2) Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland; 3) Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Geneva, Switzerland; 4) Protein Expression Core Facility, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.

   Non-coding regulatory DNA variants have been found to be associated with gene expression, yet the precise molecular basis by which they act remains elusive. We hypothesize that an integrated study of chromatin states coupled with personal genome information might enable in-depth characterization of these regulatory variants. We quantified gene expression (mRNA), genome-wide DNA binding of two regulatory proteins (polymerase II, PU.1) and three histone post-translational modifications marks, that pinpoint promoter, enhancer and active regions (H3K4me3, H3K4me1 and H3K27ac, respectively) in lymphoblastoid cell lines of 50 unrelated individuals that were whole genome-sequenced as part of the 1000 genomes project. This data allowed us mapping cis-acting QTLs for each molecular phenotype and assessing the degree of coordinated behaviors between distinct layers of gene regulation. We find that the various molecular phenotypes show abundant coordination in activity levels at enhancer and/or promoter elements, forming chromatin modules that can extent over hundreds of kb and regroup hundreds of chromatin sites. We show that overall chromatin activity at these modules is tightly correlated with changes in expression levels at genes nearby, highlighting their central role in transcription. We also mapped thousands of cis-acting QTLs for gene expression (eQTLs), histone modification levels (hmQTLs) and TF binding (tfQTLs) at 10% FDR. We find that they are widespread across the genome and that they explain a substantial fraction of inter-individual variability in chromatin activity. In addition, we find large overlaps between the various QTLs (50% of eQTLs are also hmQTLs) which reflects the genetic signal propagation through the multiple phenotypic layers and show that the genetic perturbation of chromatin tend to be causal to changes in gene expression levels. Overall, this large-scale study that integrates DNA, RNA, regulatory proteins and histone modifications provides novel insights into the mechanisms underlying regulatory variation and their effects on transcription.

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