Comparative Analysis of Immune Cells Reveals a Conserved Regulatory Lexicon

Abstract

<p id="P1">Most well-characterized enhancers are deeply conserved. In contrast, genome-wide comparative studies of steady state systems showed that only a small fraction of active enhancers are conserved. To better understand conservation of enhancer activity we used a comparative genomics approach that integrates temporal expression and epigenetic profiles in an innate immune system. We found that gene expression programs diverge among mildly induced genes while being highly conserved for strongly induced genes. The fraction of conserved enhancers varies greatly across gene expression programs, with induced genes and early response genes in particular, being regulated by a higher fraction of conserved enhancers. Clustering of conserved accessible DNA sequence within enhancers resulted in over 80 sequence motifs including motifs for known factors as well as many with unknown function. We further show that the number of instances of these motifs is a strong predictor of the responsiveness of a gene to pathogen detection. </p><p id="P2">A comparison of the transcriptome and chromatin landscape between mouse and human innate immune cells reveals higher conservation of regulatory elements that control specific gene expression programs. These conserved elements contain a large set of constrained sequence motifs, which can be used as features to successfully predict gene induction in stimulated mouse and human innate immune cells. </p><p id="P3"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/78ff8e02-7bb0-4962-af88-d181334e38fb/PubMedCentral/image/nihms937964u1.jpg"/> </div> </p>