Epigenetic analysis of the murine chromatin landscape identifies a repertoire of eosinophil-specific PU.1-bound enhancers

• Published in: The Journal of immunology (1950) 2021-07, Vol.207 (4), p.1044-1054
• Main Authors: Felton, Jennifer M., Vallabh, Sushmitha, Parameswaran, Sreeja, Edsall, Lee E., Ernst, Kevin, Wronowski, Benjamin, Malik, Astha, Kotliar, Michael, Weirauch, Matthew T., Barski, Artem, Fulkerson, Patricia C., Rothenberg, Marc E.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000207

Eosinophils develop in the bone marrow from hematopoietic progenitors into mature cells capable of a plethora of immunomodulatory roles via the choreographed process of eosinophilopoiesis. However, the gene regulatory elements and transcription factors (TFs) orchestrating this process remain largely unknown. The potency and resulting diversity fundamental to an eosinophil’s complex immunomodulatory functions and tissue specialization likely result from dynamic epigenetic regulation of the eosinophil genome—a dynamic eosinophil regulome. Herein, we applied a global approach using broad-range, next-generation sequencing to identify a repertoire of eosinophil-specific enhancers. We identified over 8,200 active enhancers located within 1 - 20 kB of expressed eosinophil genes. TF binding motif analysis revealed PU.1 ( Spi1 ) motif enrichment in eosinophil enhancers, and ChIP-seq confirmed PU.1 binding in likely enhancers of genes highly expressed in eosinophils. A substantial proportion (>25%) of these PU.1-bound enhancers were unique to murine, culture-derived eosinophils when compared among enhancers of highly expressed genes of three closely related myeloid cell subsets (macrophages, neutrophils, immature granulocytes). Gene ontology analysis of eosinophil-specific, PU.1-bound enhancers revealed enrichment for genes involved in migration, proliferation, degranulation and survival. Furthermore, eosinophil-specific super enhancers were enriched in genes whose homologues are associated with risk loci for eosinophilia and allergic diseases. Our collective data identify eosinophil-specific enhancers regulating key eosinophil genes through epigenetic mechanisms (H3K27 acetylation) and TF binding (PU.1).