Cell Reports
Volume 32, Issue 7, 18 August 2020, 108048
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Alternative Enhancer Usage and Targeted Polycomb Marking Hallmark Promoter Choice during T Cell Differentiation

https://doi.org/10.1016/j.celrep.2020.108048Get rights and content
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Highlights

  • Active T cell p-enhancers are highly dynamic during differentiation

  • Enhancer diversity might function to select specific isoform expression

  • Loss of H3K27me3 combined with enhancer gain hallmark T cell identity

  • Promoter choice is regulated by the PRC2 polycomb complex during differentiation

Summary

During thymic development and upon peripheral activation, T cells undergo extensive phenotypic and functional changes coordinated by lineage-specific developmental programs. To characterize the regulatory landscape controlling T cell identity, we perform a wide epigenomic and transcriptional analysis of mouse thymocytes and naive CD4 differentiated T helper cells. Our investigations reveal a dynamic putative enhancer landscape, and we could validate many of the enhancers using the high-throughput CapStarr sequencing (CapStarr-seq) approach. We find that genes using multiple promoters display increased enhancer usage, suggesting that apparent “enhancer redundancy” might relate to isoform selection. Furthermore, we can show that two Runx3 promoters display long-range interactions with specific enhancers. Finally, our analyses suggest a novel function for the PRC2 complex in the control of alternative promoter usage. Altogether, our study has allowed for the mapping of an exhaustive set of active enhancers and provides new insights into their function and that of PRC2 in controlling promoter choice during T cell differentiation.

Keywords

T cell enhancerome
enhancer and promoter usage
long-distance enhancer-promoter interactions
enhancer redundancy
CapSTARR-seq

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Present address: CRUK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Aderley Park, Macclesfield SK104TG, UK

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