• Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

      Yang, Jing; McGovern, Amanda; orcid: 0000-0001-7727-3283; Martin, Paul; orcid: 0000-0002-1016-6851; Duffus, Kate; Ge, Xiangyu; Zarrineh, Peyman; Morris, Andrew P.; Adamson, Antony; orcid: 0000-0002-5408-0013; Fraser, Peter; orcid: 0000-0002-0041-1227; Rattray, Magnus; orcid: 0000-0001-8196-5565; email: magnus.rattray@manchester.ac.uk; et al. (Nature Publishing Group UK, 2020-09-02)
      Abstract: Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.
    • Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

      Gerrard, Dave T.; orcid: 0000-0001-6890-7213; Berry, Andrew A.; Jennings, Rachel E.; Birket, Matthew J.; orcid: 0000-0002-5985-6626; Zarrineh, Peyman; Garstang, Myles G.; Withey, Sarah L.; Short, Patrick; orcid: 0000-0002-7626-6177; Jiménez-Gancedo, Sandra; Firbas, Panos N.; et al. (Nature Publishing Group UK, 2020-08-06)
      Abstract: How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.