The single-cell chromatin accessibility landscape in mouse perinatal testis development

Abstract

Spermatogenesis depends on an orchestrated series of developing events in germ cells and full maturation of the somatic microenvironment. To date, the majority of efforts to study cellular heterogeneity in testis has been focused on single-cell gene expression rather than the chromatin landscape shaping gene expression. To advance our understanding of the regulatory programs underlying testicular cell types, we analyzed single-cell chromatin accessibility profiles in more than 25,000 cells from mouse developing testis. We showed that scATAC-Seq allowed us to deconvolve distinct cell populations and identify cis-regulatory elements (CREs) underlying cell type specification. We identified sets of transcription factors associated with cell type-specific accessibility, revealing novel regulators of cell fate specification and maintenance. Pseudotime reconstruction revealed detailed regulatory dynamics coordinating the sequential developmental progressions of germ cells and somatic cells. This high-resolution dataset also unveiled previously unreported subpopulations within both the Sertoli and Leydig cell groups. Further, we defined candidate target cell types and genes of several GWAS signals, including those associated with testosterone levels and coronary artery disease. Collectively, our data provide a blueprint of the 'regulon' of the mouse male germline and supporting somatic cells.

scaDA: A Novel Statistical Method for Differential Analysis of Single-Cell Chromatin Accessibility Sequencing Data

“…Second, cell type-specific DA regions enable the identification of different cell subpopulations. For example, DA analysis can distinguish cell types by cluster-specific DA regions associated with cell type-specific marker genes identified from scRNA-seq [8]. Third, DA analysis can detect disease-associated DA regions by comparing disease and control scATAC-seq samples.…”