Alternative Enhancer Usage and Targeted Polycomb Marking Hallmark Promoter Choice during T Cell Differentiation

• Published in: Cell reports (Cambridge) Vol. 32; no. 7; p. 108048
• Main Authors: Maqbool, Muhammad Ahmad, Pioger, Léo, El Aabidine, Amal Zine, Karasu, Nezih, Molitor, Anne Marie, Dao, Lan T.M., Charbonnier, Guillaume, van Laethem, Francois, Fenouil, Romain, Koch, Frederic, Lacaud, Georges, Gut, Ivo, Gut, Marta, Amigorena, Sebastian, Joffre, Olivier, Sexton, Thomas, Spicuglia, Salvatore, Andrau, Jean-Christophe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.08.2020
• Subjects: Animals; Biochemistry, Molecular Biology; CapSTARR-seq; Cell Differentiation; enhancer and promoter usage; enhancer redundancy; Genomics; Immunology; Life Sciences; long-distance enhancer-promoter interactions; Male; Mice; Polycomb-Group Proteins - genetics; T cell enhancerome; T-Lymphocytes - metabolism; long-distance enhancer-promoter interactions; T cell enhancerome; enhancer redundancy; enhancer and promoter usage; CapSTARR-seq
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108048

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. [Display omitted] •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 Development and activation of T lymphocytes are coordinated by lineage-specific transcriptional programs. Here, Maqbool et al. performed a wide epigenomic and transcriptional analysis of mouse T cell differentiation. These data provide new insights into the role of multiple enhancers and PRC2 in controlling alternative promoter choice during differentiation.