Enhancer-silencer transitions in the human genome

Dual-function regulatory elements (REs), acting as enhancers in some cellular contexts and as silencers in others, have been reported to facilitate the precise gene regulatory response to developmental signals in Drosophila melanogaster. However, with few isolated examples detected, dual-function REs in mammals have yet to be systematically studied. We herein investigated this class of REs in the human genome and profiled their activity across multiple cell types. Focusing on enhancer-silencer transitions specific to the development of T cells, we built an accurate deep learning classifier of REs and identified about 12,000 silencers active in primary peripheral blood T cells that act as enhancers in embryonic stem cells. Compared with regular silencers, these dual-function REs are evolving under stronger purifying selection and are enriched for mutations associated with disease phenotypes and altered gene expression. In addition, they are enriched in the loci of transcriptional regulators, such as transcription factors (TFs) and chromatin remodeling genes. Dual-function REs consist of two intertwined but largely distinct sets of binding sites bound by either activating or repressing TFs, depending on the type of RE function in a given cell line. This indicates the recruitment of different TFs for different regulatory modes and a complex DNA sequence composition of these REs with dual activating and repressive encoding. With an estimated >6% of cell type-specific human silencers acting as dual-function REs, this overlooked class of REs requires a specific investigation on how their inherent functional plasticity might be a contributing factor to human diseases.

Automated summary

Dual-function regulatory elements, which act as enhancers in some contexts and as silencers in others, have been extensively studied in fruit flies but not in mammals. This study investigated these elements in the human genome and identified about 12,000 dual-function elements that are active in T cells and embryonic stem cells. Compared to regular silencers, these dual-function elements are under stronger purifying selection, enriched with disease-associated mutations and altered gene expression, and located near transcriptional regulators.