Charting the cis-regulome of activated B cells by coupling structural and functional genomics

Nat Immunol. 2020 Feb;21(2):210-220. doi: 10.1038/s41590-019-0565-0. Epub 2019 Dec 23.


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.

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Gene Regulatory Networks
  • Genomics / methods*
  • High-Throughput Nucleotide Sequencing / methods*
  • Lymphocyte Activation / genetics*
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL