Systematic integration of GATA transcription factors and epigenomes via IDEAS paints the regulatory landscape of mouse hematopoietic cells

Members of the GATA family of transcription factors play key roles in the differentiation of specific cell lineages by regulating the expression of target genes. Three GATA factors play distinct roles in hematopoietic differentiation. In order to better understand how these GATA factors function to regulate genes throughout the genome, we are studying the epigenomic and transcriptional landscapes of hematopoietic cells in a model-driven, integrative fashion. We have formed the collaborative multi-lab VISION project to conduct ValIdated Systematic IntegratiON of epigenomic data in mouse and human hematopoiesis. The epigenomic data included nuclease accessibility in chromatin, CTCF occupancy, and histone H3 modifications for twenty cell types covering hematopoietic stem cells, multilineage progenitor cells, and mature cells across the blood cell lineages of mouse. The analysis used the Integrative and Discriminative Epigenome Annotation System (IDEAS), which learns all common combinations of features (epigenetic states) simultaneously in two dimensions - along chromosomes and across cell types. The result is a segmentation that effectively paints the regulatory landscape in readily interpretable views, revealing constitutively active or silent loci as well as the loci specifically induced or repressed in each stage and lineage. Nuclease accessible DNA segments in active chromatin states were designated candidate cis-regulatory elements in each cell type, providing one of the most comprehensive registries of candidate hematopoietic regulatory elements to date. Applications of VISION resources are illustrated for regulation of genes encoding GATA1, GATA2, GATA3, and Ikaros. VISION resources are freely available from our website http://usevision.org.

GATA转录因子家族成员通过调节靶基因的表达，在特定细胞谱系的分化中发挥关键作用。三种GATA因子在造血分化中具有不同的作用。为了更好地理解这些GATA因子如何在整个基因组中调节基因，我们正在以模型驱动的综合方式研究造血细胞的表观基因组和转录图谱。我们组建了多实验室合作的VISION项目，以便在小鼠和人类造血过程中对表观基因组数据进行验证性的系统整合。表观基因组数据包括染色质中的核酸酶可及性、CTCF结合情况以及小鼠血细胞谱系中涵盖造血干细胞、多谱系祖细胞和成熟细胞的20种细胞类型的组蛋白H3修饰。分析使用了综合判别表观基因组注释系统（IDEAS），该系统同时在两个维度——沿着染色体和跨细胞类型——学习所有常见的特征组合（表观遗传状态）。结果是一种分割，有效地以易于理解的视图描绘了调控图谱，揭示了组成性活跃或沉默的基因座以及在每个阶段和谱系中特异性诱导或抑制的基因座。处于活跃染色质状态的核酸酶可及DNA片段在每种细胞类型中被指定为候选顺式调控元件，提供了迄今为止最全面的候选造血调控元件登记之一。VISION资源在编码GATA1、GATA2、GATA3和伊卡洛斯（Ikaros）的基因调控方面的应用得到了阐述。VISION资源可从我们的网站http://usevision.org免费获取。