Single nucleus multi-omics regulatory atlas of the murine pituitary [single nuclei ATAC-Seq]

The pituitary regulates growth, reproduction and other endocrine systems. To investigate transcriptional network epigenetic mechanisms in this gland, we generated paired single nucleus (sn) transcriptome and chromatin accessibility profiles in single mouse pituitaries, and genome-wide sn methylation datasets. Our analysis provided insight into cell type epigenetics, regulatory circuit and gene control mechanisms. Latent variable transcriptome and accessibility data representation resolved both inter-sexual and inter-individual variation in gene control programs. Multi-omics analysis of cell type-specific gene regulatory networks distinguished distinct mechanisms. Particularly, the FoxL2 gonadotrope network is controlled both by FoxL2 expression and by target gene epigenetic status. Co-accessibility analysis comprehensively identified putative regulatory regions, including a region that overlapped the fertility-linked rs11031006 human polymorphism. In vitro CRISPR-deletion at this locus increased Fshb levels, supporting this domain’s predicted regulatory role. The public pituitary atlas [link] is a resource for elucidating cell-type specific gene regulatory mechanisms and principles of transcription circuit control. Single nucleus chromatin accessibility profiling of adult mouse pituitaries by single nuclei ATAC-seq, using Illumina

垂体（pituitary）调控生长、生殖及其他内分泌系统。为探究该腺体中转录网络的表观遗传机制，我们在单个小鼠垂体中生成了配对的单细胞核（single nucleus, sn）转录组与染色质可及性图谱，以及全基因组单细胞核甲基化数据集。本研究的分析为细胞类型表观遗传学、调控环路及基因调控机制提供了重要见解。基于潜变量的转录组与染色质可及性数据表征，解析了基因调控程序中存在的性别间与个体间差异。针对细胞类型特异性基因调控网络开展的多组学分析，甄别出了多种不同的调控机制。尤为值得关注的是，FoxL2促性腺激素细胞调控网络同时受FoxL2表达水平与靶基因表观遗传状态的共同调控。共可及性分析全面鉴定出了潜在调控区域，其中一处区域与生育相关的人类多态性位点rs11031006存在重叠。在该位点进行体外CRISPR删除实验可上调Fshb的表达水平，佐证了该调控结构域的预测功能。公开可用的垂体图谱[link]是解析细胞类型特异性基因调控机制与转录环路调控原则的重要研究资源。本研究采用Illumina测序平台，通过单细胞核ATAC-seq技术完成了成年小鼠垂体的染色质可及性谱分析。