Charting the cis-regulome of activated B cells by coupling structural and functional genomics
Charting the cis-regulome of activated B cells by coupling structural and functional genomics
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DOI：
10.1038/s41590-019-0565-0
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发表时间：
2019-12-23
影响因子：
30.5
通讯作者：
Singh, Harinder
中科院分区：
文献类型：
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作者：
Chaudhri, Virendra K.;Dienger-Stambaugh, Krista;Singh, Harinder
免疫细胞特异性基因组状态的顺式调节体已经通过基于结构的染色质图谱进行了广泛的分析。通过将这些方法与高通量增强子筛选(自转录活性调节区测序(STARR-SEQ))相结合，我们组装了内毒素激活的B细胞的功能顺式调节组。与缺乏增强子活性的可及染色质区域相比，功能增强子富含增强子RNA(ERNAs)，并在体内优先与B细胞谱系决定转录因子相互作用。有趣的是，这些转录因子的优先组合结合与其位点的不同富集度无关。取而代之的是，通过主成分分析(PCA)从所有可访问区域通过涉及一组不同的信号诱导转录因子的转录因子基序分数来解析活性增强子。高分辨染色体构象捕获(Hi-C)分析显示，多个激活的增强子-启动子结构包含大量的多增强子基因和多基因增强子，参与控制不同的分子通路。途径特异性增强子的基序分析提供了包括B细胞激活、循环和分化在内的生物过程的不同转录因子编码的目录。Singh和他的同事利用全基因组分析，通过FIRE-SEQ、STARR-SEQ和Hi-C结构相互作用组分析，识别存在于NAIVE和脂多糖激活的B细胞中的功能活性增强子，并识别调节基因表达模块的其他转录因子。
Cis-regulomes underlying immune-cell-specific genomic states have been extensively analyzed by structure-based chromatin profiling. By coupling such approaches with a high-throughput enhancer screen (self-transcribing active regulatory region sequencing (STARR-seq)), we assembled a functional cis-regulome for lipopolysaccharide-activated B cells. Functional enhancers, in contrast with accessible chromatin regions that lack enhancer activity, were enriched for enhancer RNAs (eRNAs) and preferentially interacted in vivo with B cell lineage-determining transcription factors. Interestingly, preferential combinatorial binding by these transcription factors was not associated with differential enrichment of their sites. Instead, active enhancers were resolved by principal component analysis (PCA) from all accessible regions by co-varying transcription factor motif scores involving a distinct set of signaling-induced transcription factors. High-resolution chromosome conformation capture (Hi-C) analysis revealed multiplex, activated enhancer-promoter configurations encompassing numerous multi-enhancer genes and multi-genic enhancers engaged in the control of divergent molecular pathways. Motif analysis of pathway-specific enhancers provides a catalog of diverse transcription factor codes for biological processes encompassing B cell activation, cycling and differentiation.Singh and colleagues leverage genome-wide assays to identify functionally active enhancers that are present in naive and lipopolysaccharide-activated B cells by FAIRE-seq, STARR-seq and Hi-C structural interactome analyses and identify additional transcription factors that regulate gene expression modules.