2014.9.16 Individuality and variation of personal regulomes in human T cells
题目：Individuality and variation of personal regulomes in human T cells
报告人：Kun Qu, Ph.D.
Program in Epithelial Biology, Stanford University School of Medicine, Stanford
The fidelity and individual variation of human gene regulation in vivo are not well understood. Prior methods to assess chromatin activity often required immortalization or extensively in vitro cell expansion, limiting the resulting analyses. Here we surveyed the variation and dynamics of active regulatory elements genome-wide in CD4+ T cells, using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) in chronological samples donated by healthy volunteers over time. Approximately 10% of the 66,344 active regulatory elements in CD4+ T cells, showed reproducibly variable activity across individuals and time. Notably, gender emerged as the most significant attributable source of the inter-individual variation.
By comparing male and female ATAC-seq signals on sex chromosomes, we identified over one hundred regulatory elements that escape X chromosome inactivation in association with both known and novel escapee genes, and documented the regulatory divergence between homologs on X and Y chromosomes. We discovered gender-specific gene regulatory networks by identifying transcription factor (TF) footprints associated with ATAC-seq peaks on autosome. We found several hundred genes that show significant differences in their regulatory pattern in male vs. female T cells, and the top divergent genes include many genes with well-known important functions in immune function or development, providing evidence for intrinsic propensity of female T cells for autoimmunity. In contrast, we observed just a handful of TFs with gender-associated divergence. Approximately 30% of the personal regulome variation can be accounted for by genetic variation, suggesting a large contribution of environmental and epigenetic differences. Low frequency single nucleotide polymorphisms (SNPs) were significantly enriched at variable regulatory sites, while SNPs with eQTL and disease association were depleted. Overall, our results provided the first insights of human regulome variations in vivo.