We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas. We identify 562,709 transposase-accessible DNA elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-DNA footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active DNA regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may impact patient survival. These results suggest a systematic approach to understand the noncoding genome in cancer to advance diagnosis and therapy.

Genome-wide association studies (GWAS) of neurological diseases have identified thousands of variants associated with disease phenotypes. However, the majority of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional (3D) chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional single-nucleotide polymorphisms (SNPs) for Alzheimer’s disease (AD) and Parkinson’s disease (PD), nominating target genes and cell types for previously orphaned GWAS loci. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands our understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

Modular domains of long non-coding RNAs can serve as scaffolds to bring distant regions of the linear genome into spatial proximity. Here, we present HiChIRP, a method leveraging bioorthogonal chemistry and optimized chromosome conformation capture conditions, which enables interrogation of chromatin architecture focused around a specific RNA of interest down to approximately ten copies per cell. HiChIRP of three nuclear RNAs reveals insights into promoter interactions (7SK), telomere biology (telomerase RNA component) and inflammatory gene regulation (lincRNA-EPS).

42Genome-wide association studies (GWAS) have identified thousands of variants associated with 43 disease phenotypes. However, the majority of these variants do not alter coding sequences, making 44 it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the 45 adult human brain through profiling of the chromatin accessibility landscapes and three-46 dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy 47 individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain 48 regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, 49 capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to 50 integrate this multi-omic framework and predict dozens of functional single nucleotide 51 polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. 52These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for 53 Alzheimer's disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia 54 and MAL in oligodendrocytes for Parkinson's disease (PD). Moreover, we dissect the complex 55 inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene 56 contacts in neurons that increase MAPT expression and may mediate this disease association. This 57 work greatly expands our understanding of inherited variation in AD and PD and provides a 58 roadmap for the epigenomic dissection of noncoding regulatory variation in disease. 59 60 61 62Alzheimer's disease (AD) and Parkinson's disease (PD) affect ~50 and ~10 million individuals 63 world-wide, as two of the most common neurodegenerative disorders. Several large consortia have 64 assembled genome-wide association studies (GWAS) that associate genetic variants with clinical 65 diagnoses of probable AD dementia 1-4 or probable PD 5-7 , or with their characteristic pathologic 66 features. These efforts have led to the identification of dozens of potential risk loci for these 67 prevalent neurodegenerative diseases. One goal of these studies was to build more precise 68 molecular biomarkers of AD or PD, efforts that are beginning to yield encouraging results with 69 polygenic risk scores 8 . The other major goal was to gain deeper insight into the molecular 70 pathogenesis of disease and thereby inform novel therapeutic targets. Some of the risk loci contain 71 coding variants and so have credibility as putative disease mediators. However, most risk loci are 72 in noncoding regions and so it remains unclear if the nominated (often nearest) gene is the 73 functional disease-relevant gene, or if some other gene is involved 9 . Furthermore, even if the 74 nominated gene is a true positive, the noncoding risk locus might regulate additional genes. These 75 challenges remain a fundamental gap in interpreting the etiology of neurodegenerative diseases 76 and d...