An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis [RNA-seq]

Thousands of epigenomic datasets have been generated in the past decade, but it is difficult for researchers to effectively utilize all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established for ValIdated Systematic IntegratiON of epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By employing IDEAS as our Integrative and Discriminative Epigenome Annotation System, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of over 200,000 candidate cis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website (usevision.org) to aid research in genomics and hematopoiesis. Two samples, each in replicate过去十年间，全球已生成数以万计的表观基因组数据集，但研究人员难以高效利用所有与自身研究项目相关的数据。系统性整合分析可有效解决这一痛点，为此我们启动了VISION项目（全称ValIdated Systematic IntegratiON，即造血系统表观基因组数据的经验证系统性整合项目）。本研究中，我们系统性整合了来自独立实验室、各类研究联盟等多渠道的海量表观遗传特征与转录组数据，以全面解析小鼠造血细胞分化过程中的基因调控景观。我们采用IDEAS（整合判别式表观基因组注释系统，Integrative and Discriminative Epigenome Annotation System）作为分析工具，能够精准且全面地同时沿染色体维度与跨细胞类型识别并分配表观遗传状态。结合核酸酶可及性数据与表观遗传状态，我们鉴定出了超过20万个候选顺式调控元件（candidate cis-regulatory elements，缩写cCREs），可高效捕获增强子与启动子区域。这些cCREs在不同细胞类型间的表观遗传状态转变，为调控机制研究提供了关键见解：包括多数细胞谱系分化过程中活性cCRE数量的减少、从暂态（poised）向活跃或非活跃状态的转变，以及CTCF结合元件的核酸酶可及性变化。通过对cCRE处的表观遗传状态与基因表达进行回归建模，我们构建了一套通用研究资源，可用于优化筛选潜在调控靶基因的cCREs。上述资源已通过VISION项目官网（usevision.org）对外开放，以助力基因组学与造血系统相关研究。本研究包含两份样本，每份均设置重复实验。