![]() A critical next step is to determine their functions and sequence determinants. Genome-wide maps of chromatin state and transcription factor (TF) binding have nominated more than a million cell type-specific regulatory elements (REs) in the human genome as potential context-specific regulators of gene expression( Andersson and Sandelin, 2020 ENCODE Project Consortium et al., 2020 Stunnenberg et al., 2016). Our study provides a framework for parsing gene regulatory elements in their endogenous chromatin contexts and identifying operative artificial variants. Systematic analysis of GATA and bHLH/Ebox motifs suggests that interplay between these factors plays a general role in rapid T cell transcriptional responses. The most potent base edits may be explained by their effect on binding competition between the transcriptional activator GATA3 and the repressor BHLHE40. We pinpoint individual cytosine to thymine base edits that markedly reduce element accessibility and acetylation, with corresponding reduction of CD69 expression. Focusing on a differentially accessible and acetylated upstream enhancer, we find that the complementary strategies converge on a ∼170 base interval as critical for CD69 induction in stimulated Jurkat T cells. ![]() ![]() Here we combine epigenetic perturbations, base editing, and deep learning models to dissect regulatory sequences within the exemplar immune locus encoding CD69. Although vast numbers of putative gene regulatory elements have been cataloged, the sequence motifs and individual bases that underlie their functions remain largely unknown. ![]()
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