In inflammation, elevated GM-CSF directs the development of dendritic cells (DCs) from myeloid precursors that infiltrate tissues. These inflammatory DCs play a central role in infection and autoimmunity. We previously showed that estradiol and estrogen receptor alpha (ERα) act in murine Flt3+ myeloid progenitors to promote GM-CSF-mediated DC differentiation. ERs are ligand-dependent transcription factors that form complexes with chromatin-modifying coregulators near gene promoters. Thus, we hypothesized that ERα regulates chromatin structure at loci important for DC differentiation. We used anti-ERα chromatin immunoprecipitation and next generation sequencing to identify genome-wide sites of ERα binding in myeloid progenitors stimulated with GM-CSF -/+ estradiol. Bioinformatics analyses identified unique ERα binding sites in the presence of estradiol near the transcription start site of >900 genes. Binding of ERα was enriched at CpG islands and consensus binding sites for SP1 and GABPA transcription factors. ERα bound to genes in pathways related to ER, GM-CSF and ERK/MAPK signaling, protein ubiquitination and cell cycle progression. ERα also bound to multiple genes in the NF-κB and Toll-like receptor pathways. These data suggest that ERα regulates genes involved in the NF-κB and GM-CSF signaling pathways during GM-CSF-mediated differentiation, and primes myeloid progenitors or mature DCs for responses to inflammatory stimuli.
- Copyright © 2013 by The American Association of Immunologists, Inc.