Early enhancer establishment and regulatory locus complexity shape transcriptional programs in hematopoietic differentiation.
Early enhancer establishment and regulatory locus complexity shape transcriptional programs in hematopoietic differentiation.
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DOI：
10.1038/ng.3402
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发表时间：
2015-11
期刊：
影响因子：
30.8
通讯作者：
Leslie CS
中科院分区：
文献类型：
--
作者：
González AJ;Setty M;Leslie CS
我们使用DNase-seq，组蛋白标记ChIP-seq和RNA-seq对造血分化中的增强子景观和基因表达动态进行了综合分析，以模拟增强子和调控位点复杂性的早期建立如何在细胞状态转换时控制基因表达变化。我们发现，高复杂性基因-即那些在整个谱系中具有大量DNA酶映射增强子的基因-在结构和功能上与低复杂性基因不同，实现更大的表达变化，并且富含细胞类型特异性和“过渡”增强子，这些增强子在造血干细胞和祖细胞中建立，并在一种分化的细胞命运中维持，但在其他细胞中丢失。然后，我们开发了一个定量模型，从DNA序列含量和活性增强子的谱系历史准确预测基因表达变化。我们的方法表明，PU.1在B细胞规范的过渡峰处的一种新的机制作用，并可用于校正增强子基因分配。
We carried out an integrative analysis of enhancer landscape and gene expression dynamics in hematopoietic differentiation using DNase-seq, histone mark ChIP-seq, and RNA-seq to model how early establishment of enhancers and regulatory locus complexity govern gene expression changes at cell state transitions. We found that high complexity genes – i.e. those with large total number of DNase-mapped enhancers across the lineage – differ architecturally and functionally from low complexity genes, achieve larger expression changes, and are enriched for both cell-type specific and “transition” enhancers, which are established in hematopoietic stem and progenitor cells and maintained in one differentiated cell fate but lost in others. We then developed a quantitative model to accurately predict gene expression changes from the DNA sequence content and lineage history of active enhancers. Our method suggests a novel mechanistic role for PU.1 at transition peaks in B cell specification and can be used to correct enhancer-gene assignments.