Zhou, PingzhuGu, FeiZhang, LinaAkerberg, Brynn NMa, QingLi, KaiHe, AibinLin, ZhiqiangStevens, Sean MZhou, BinPu, William2017-03-282017Zhou, P., F. Gu, L. Zhang, B. N. Akerberg, Q. Ma, K. Li, A. He, et al. 2017. “Mapping cell type-specific transcriptional enhancers using high affinity, lineage-specific Ep300 bioChIP-seq.” eLife 6 (1): e22039. doi:10.7554/eLife.22039. http://dx.doi.org/10.7554/eLife.22039.http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731675Understanding 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. DOI: http://dx.doi.org/10.7554/eLife.22039.001en-UStranscriptional enhancerendothelial cellangiogenesisp300MouseJournal Article2017-03-2810.7554/eLife.22039