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

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 performed 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.

Muhammad Ahmad Maqbool 1Léo Pioger 2Amal Zine El Aabidine 2Nezih Karasu 3Anne Marie Molitor 3Lan T M Dao 4Guillaume Charbonnier 4Francois van Laethem 2Romain Fenouil 2Frederic Koch 2Georges Lacaud 5Ivo Gut 6Marta Gut 6Sebastian Amigorena 7Olivier Joffre 8Thomas Sexton 3Salvatore Spicuglia 4Jean-Christophe Andrau 9