show Abstracthide AbstractThe genomic repertoire of enhancers and promoters that control the transcriptional output of terminally differentiated cells includes cell type-specific and housekeeping elements. Whether the constitutive activity of these two groups of cis-regulatory elements relies on entirely distinct or instead shared regulators is unknown. By dissecting the cis-regulatory repertoire of macrophages, we found that the ELF subfamily of ETS proteins selectively bound within 60 bp from the transcription start sites of highly active housekeeping genes. ELFs also bound constitutively active, but not poised macrophage-specific enhancers and promoters. The role of ELFs in promoting constitutive transcription is suggested by multiple evidences: ELF sites enabled transcriptional activation by endogenous and minimal synthetic promoters; ELF recruitment was stabilized by the transcriptional machinery, and ELF proteins mediated recruitment of transcriptional and chromatin regulators to core promoters. These data indicate that a distinct subfamily of ETS proteins imparts high transcriptional activity to a broad range of housekeeping and tissue-specific cis-regulatory elements, which is consistent with the role of an ETS family ancestor in core promoter regulation in a lower eukaryote. Overall design: Chromatin immuno-precipitations of transcription factors Fli1, Elf1, Elf4, GABP-a, H3 lysine 4 trimethylated, H3 lysine 4 monomethylated, PU.1, H3 lysine 27 and RNA polymerase II followed by multiparallel sequencing, performed in bone marrow-derived macrophages from wild type (WT) mice. Cells were treated with alpha amanitin for 5 hours or left unstimulated. This study includes re-analysis of the following samples from GSE38377: GSM940891, GSM940902, GSM940904, GSM940913, and GSM940924. The .bed files with called peaks for these samples are available on the series record. The input sample used for all samples for which peak calling was performed, including the re-analyzed samples, is GSM2344452. No peak calling was done for RNAPolII ChIP samples. BigWig files with genome-wide IP signal are available for the RNAPolII ChIP samples.