Mapping cell type-specific transcriptional enhancers using high affinity, lineage-specific Ep300 bioChIP-seq

• Published in: eLife Vol. 6
• Main Authors: Zhou, Pingzhu, Gu, Fei, Zhang, Lina, Akerberg, Brynn N, Ma, Qing, Li, Kai, He, Aibin, Lin, Zhiqiang, Stevens, Sean M, Zhou, Bin, Pu, William T
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 25-01-2017; eLife Sciences Publications, Ltd
• Subjects: angiogenesis; Animals; Biochemistry; Biotinylation; Chinese medicine; Chromatin Immunoprecipitation - methods; Consortia; Deoxyribonucleic acid; Developmental Biology and Stem Cells; DNA; DNA sequencing; E1A-Associated p300 Protein - metabolism; endothelial cell; Endothelial cells; Enhancer Elements, Genetic; Enhancers; Gene expression; Gene mapping; Genes and Chromosomes; Genomes; Heart; Language; Mammals; Mice; Musculoskeletal system; p300; Protein interaction; Protein Processing, Post-Translational; Proteins; Regulatory sequences; RNA polymerase; Sequence Analysis, DNA; Skeletal muscle; Specialization; Stem cells; Streptavidin; Tools and Resources; Transcription Factors; Transcription, Genetic; transcriptional enhancer; Transgenes; p300; mouse; stem cells; genes; angiogenesis; developmental biology; endothelial cell; chromosomes; transcriptional enhancer
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.22039

Understanding the mechanisms that regulate cell type-specific transcriptional programs requires developing a lexicon of their genomic regulatory elements. We developed a lineage-selective method to map transcriptional enhancers, regulatory genomic regions that activate transcription, in mice. Since most tissue-specific enhancers are bound by the transcriptional co-activator Ep300, we used Cre-directed, lineage-specific Ep300 biotinylation and pulldown on immobilized streptavidin followed by next generation sequencing of co-precipitated DNA to identify lineage-specific enhancers. By driving this system with lineage-specific Cre transgenes, we mapped enhancers active in embryonic endothelial cells/blood or skeletal muscle. Analysis of these enhancers identified new transcription factor heterodimer motifs that likely regulate transcription in these lineages. Furthermore, we identified candidate enhancers that regulate adult heart- or lung- specific endothelial cell specialization. Our strategy for tissue-specific protein biotinylation opens new avenues for studying lineage-specific protein-DNA and protein-protein interactions.