Charting the cis-regulome of activated B cells by coupling structural and functional genomics.,Nature Immunology

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Charting the cis-regulome of activated B cells by coupling structural and functional genomics.
Nature Immunology ( IF 27.7 ) Pub Date : 2019-12-23 , DOI: 10.1038/s41590-019-0565-0
Virendra K Chaudhri _{1,

2} , Krista Dienger-Stambaugh ₁ , Zhiguo Wu ₁ , Mahesh Shrestha ₁ , Harinder Singh _{1,

2}

Affiliation

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.

中文翻译：

通过耦合结构和功能基因组学绘制活化 B 细胞的顺式调节组。

已通过基于结构的染色质分析广泛分析了免疫细胞特异性基因组状态的顺式调节组。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，我们为脂多糖激活的 B 细胞组装了一个功能性顺式调节组。与缺乏增强子活性的可接近染色质区域相比，功能增强子富含增强子 RNA (eRNA)，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差异富集无关。反而，活性增强子通过主成分分析 (PCA) 从所有可访问区域通过共变转录因子基序评分解决，这些评分涉及一组不同的信号诱导转录因子。高分辨率染色体构象捕获 (Hi-C) 分析揭示了多重激活的增强子-启动子配置，其中包含许多参与控制不同分子途径的多增强子基因和多基因增强子。通路特异性增强子的基序分析为包括 B 细胞活化、循环和分化的生物过程提供了多种转录因子代码的目录。激活的增强子-启动子配置，包括许多参与控制不同分子途径的多增强子基因和多基因增强子。通路特异性增强子的基序分析为包括 B 细胞活化、循环和分化的生物过程提供了多种转录因子代码的目录。激活的增强子-启动子配置，包括许多参与控制不同分子途径的多增强子基因和多基因增强子。通路特异性增强子的基序分析为包括 B 细胞活化、循环和分化的生物过程提供了多种转录因子代码的目录。

更新日期：2019-12-23

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