Identification of Genetic Variants That Affect Histone Modifications in Human Cells

DNA Differences The extent to which genetic variation affects an individual's phenotype has been difficult to predict because the majority of variation lies outside the coding regions of genes. Now, three studies examine the extent to which genetic variation affects the chromatin of individuals with diverse ancestry and genetic variation (see the Perspective by Furey and Sethupathy). Kasowski et al. (p. 750, published online 17 October) examined how genetic variation affects differences in chromatin states and their correlation to histone modifications, as well as more general DNA binding factors. Kilpinen et al. (p. 744, published online 17 October) document how genetic variation is linked to allelic specificity in transcription factor binding, histone modifications, and transcription. McVicker et al. (p. 747, published online 17 October) identified how quantitative trait loci affect histone modifications in Yoruban individuals and established which specific transcription factors affect such modifications. Human genetic variation affects transcription factor binding, leading to histone modifications. [Also see Perspective by Furey and Sethupathy] Histone modifications are important markers of function and chromatin state, yet the DNA sequence elements that direct them to specific genomic locations are poorly understood. Here, we identify hundreds of quantitative trait loci, genome-wide, that affect histone modification or RNA polymerase II (Pol II) occupancy in Yoruba lymphoblastoid cell lines (LCLs). In many cases, the same variant is associated with quantitative changes in multiple histone marks and Pol II, as well as in deoxyribonuclease I sensitivity and nucleosome positioning. Transcription factor binding site polymorphisms are correlated overall with differences in local histone modification, and we identify specific transcription factors whose binding leads to histone modification in LCLs. Furthermore, variants that affect chromatin at distal regulatory sites frequently also direct changes in chromatin and gene expression at associated promoters.

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