A Single-Cell Atlas of In Vivo Mammalian Chromatin Accessibility

Abstract

We applied a combinatorial indexing assay, sci-ATAC-seq, to profile genome-wide chromatin accessibility in ∼100,000 single cells from 13 adult mouse tissues. We identify 85 distinct patterns of chromatin accessibility, most of which can be assigned to cell types, and ∼400,000 differentially accessible elements. We use these data to link regulatory elements to their target genes, to define the transcription factor grammar specifying each cell type, and to discover in vivo correlates of heterogeneity in accessibility within cell types. We develop a technique for mapping single cell gene expression data to single-cell chromatin accessibility data, facilitating the comparison of atlases. By intersecting mouse chromatin accessibility with human genome-wide association summary statistics, we identify cell-type-specific enrichments of the heritability signal for hundreds of complex traits. These data define the in vivo landscape of the regulatory genome for common mammalian cell types at single-cell resolution.

A Rainbow Reporter Tracks Single Cells and Reveals Heterogeneous Cellular Dynamics among Pluripotent Stem Cells and their Differentiated Derivatives

“…A new era of single cell analyses, such as single cell transcriptomics and single cell epigenomics assays, has highlighted the wide range of molecular profiles that were previously unappreciated in bulk population assays (Angermueller et al, 2016;Nestorowa et al, 2016;Cusanovich et al, 2018;Nakanishi et al, 2019). These findings have been of special relevance to stem cell biology and directed differentiation approaches as they discovered transcriptional and epigenetic heterogeneity that were inferred to affect cellular functions, despite homogeneous expression of cell-type specific markers within the populations (Angermueller et al, 2016;Kumar, Tan and Cahan, 2017;Friedman et al, 2018).…”

Single-cell ATAC-seq Signal Extraction and Enhancement with SCATE

“…Single-cell ATAC-seq data preprocessing Single-cell ATAC-seq data for GM12878 and K562 cells were obtained from GEO (GSE65360) [4]; Single-cell ATAC-seq data for human hematopoietic cell types were obtained from GEO (GSE96769) [27]; Single-cell ATAC-seq data for mouse brain and thymus were obtained from GEO (GSE111586) [29]. For each cell, pairedend reads were trimmed using the program provided by [4] to remove adaptor sequences.…”

“…We also obtained bulk ATAC-seq data from human CMP and monocytes generated by [28] and used them as gold standard. Dateset 3 consists of mouse scATAC-seq data from brain (3321 cells) and thymus (7775 cells) generated by [29]. For evaluation, the ENCODE bulk DNase-seq data for mouse brain and thymus were used as gold standard.…”

Single cell chromatin accessibility of the developmental cephalochordate

“…The epidermis layer persists along the embryo development. However, the neural ectoderm clusters then developed into neural plate (EN2, 6,[9][10][11][12], followed by the neural crest (LN3) and neural tube (LN4, 9,11,14) in late neurula stage. subsequently in larva stage, neural tube clusters can be further developed into cerebral vesicle and nerve cord.…”

“…To understand the genomic and epigenomic landscapes of animal development, single cell sequencing methods have been widely employed in developmental biology. The developmental process for mouse, zebrafish, clawed frog, worm and ascidian have been investigated at single cell resolution [7][8][9][10][11] , which revealed cell lineages and developmental trajectories. These studies elucidate the dynamic gene expression profiles during the development of rodent, fish, nematode and proto-vertebrate.…”