Genome-wide analysis of transcriptional regulators in human HSPCs reveals a densely interconnected network of coding and noncoding genes
Genome-wide analysis of transcriptional regulators in human HSPCs reveals a densely interconnected network of coding and noncoding genes
复制标题
DOI：
10.1182/blood-2013-03-490425
复制
发表时间：
2013-10-03
期刊：
影响因子：
20.3
通讯作者：
Pimanda, John E.
中科院分区：
文献类型：
--
作者：
Beck, Dominik;Thoms, Julie A. I.;Pimanda, John E.
关键转录因子（TFs）的全基因组组合结合模式尚未在原代人造血干细胞和祖细胞（HSPCs）中报道，并且限制了控制这些细胞的分子电路的全局结构分析。在这里，我们提供了人类CD34(+) HSPCs中七个关键tf （FLI1， ERG, GATA2, RUNX1， SCL， LYL1和LMO2）的高分辨率全基因组结合图，以及定量RNA和microRNA表达谱。我们编目了TFs在编码基因和microRNA启动子上的结合，并报道了所有7种TFs的组合结合都是有利的，并且与HSPCs中基因和microRNA的差异表达有关。我们还发现了HSPCs中先前未被认识到的FLI1和RUNX1配对之间的关联，我们建立了标记活性增强子的组蛋白修饰密度与高峰重叠tf数量之间的相关性，我们在CD34（+）细胞中为后期表达准备的heptad靶基因启动子上证明了二价组蛋白标记，我们确定了特定microrna与由heptad调节的编码基因之间的复杂关系。综上所述，这些数据揭示了将染色质免疫沉淀的多因子测序与编码和非编码基因表达结合起来识别控制细胞身份的调控回路的能力。
Genome-wide combinatorial binding patterns for key transcription factors (TFs) have not been reported for primary human hematopoietic stem and progenitor cells (HSPCs), and have constrained analysis of the global architecture of molecular circuits controlling these cells. Here we provide high-resolution genome-wide binding maps for a heptad of key TFs (FLI1, ERG, GATA2, RUNX1, SCL, LYL1, and LMO2) in human CD34(+) HSPCs, together with quantitative RNA and microRNA expression profiles. We catalog binding of TFs at coding genes and microRNA promoters, and report that combinatorial binding of all 7 TFs is favored and associated with differential expression of genes and microRNA in HSPCs. We also uncover a previously unrecognized association between FLI1 and RUNX1 pairing in HSPCs, we establish a correlation between the density of histone modifications that mark active enhancers and the number of overlapping TFs at a peak, we demonstrate bivalent histone marks at promoters of heptad target genes in CD34(+) cells that are poised for later expression, and we identify complex relationships between specific microRNAs and coding genes regulated by the heptad. Taken together, these data reveal the power of integrating multifactor sequencing of chromatin immunoprecipitates with coding and noncoding gene expression to identify regulatory circuits controlling cell identity.