@article{d8bde19f9db44393ab07eeef81001c3c,
title = "High Amount of Transcription Factor IRF8 Engages AP1-IRF Composite Elements in Enhancers to Direct Type 1 Conventional Dendritic Cell Identity",
abstract = "Development and function of conventional dendritic cell (cDC) subsets, cDC1 and cDC2, depend on transcription factors (TFs) IRF8 and IRF4, respectively. Since IRF8 and IRF4 can each interact with TF BATF3 at AP1-IRF composite elements (AICEs) and with TF PU.1 at Ets-IRF composite elements (EICEs), it is unclear how these factors exert divergent actions. Here, we determined the basis for distinct effects of IRF8 and IRF4 in cDC development. Genes expressed commonly by cDC1 and cDC2 used EICE-dependent enhancers that were redundantly activated by low amounts of either IRF4 or IRF8. By contrast, cDC1-specific genes relied on AICE-dependent enhancers, which required high IRF concentrations, but were activated by either IRF4 or IRF8. IRF8 was specifically required only by a minority of cDC1-specific genes, such as Xcr1, which could distinguish between IRF8 and IRF4 DNA-binding domains. Thus, these results explain how BATF3-dependent Irf8 autoactivation underlies emergence of the cDC1-specific transcriptional program.",
keywords = "AICE, AP-1-IRF composite element, EICE, Ets-IRF composite element, IRF, IRF4, IRF8, cis-regulatory element, dendritic cell identity, interferon regulatory factor, transcriptional program",
author = "Sunkyung Kim and Prachi Bagadia and Anderson, {David A.} and Liu, {Tian Tian} and Xiao Huang and Theisen, {Derek J.} and O'Connor, {Kevin W.} and Ohara, {Ray A.} and Arifumi Iwata and Murphy, {Theresa L.} and Murphy, {Kenneth M.}",
note = "Funding Information: We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The center is partially supported by the National Cancer Institute {\textquoteright}s Cancer Center Support grant no. P30 CA91842 to the Siteman Cancer Center and by the Institute of Clinical and Translational Sciences /Clinical and Translational Science Award grant no. UL1TR000448 from the National Center for Research Resources ( NCRR ), a component of the National Institutes of Health ( NIH ) and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NCRR or NIH. This work benefitted from data assembled by the ImmGen consortium ( Heng et al., 2008 ). This work was supported by the Howard Hughes Medical Institute and NIH (grant no. R01AI150297 to K.M.M.), the National Science Foundation (grant no. DGE-1745038 to P.B. and DGE-1143954 to D.A.A.), and National Cancer Institute of NIH (grant no. F31 CA228240 to D.A.A.). Funding Information: We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The center is partially supported by the National Cancer Institute's Cancer Center Support grant no. P30 CA91842 to the Siteman Cancer Center and by the Institute of Clinical and Translational Sciences/Clinical and Translational Science Award grant no. UL1TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NCRR or NIH. This work benefitted from data assembled by the ImmGen consortium (Heng et al. 2008). This work was supported by the Howard Hughes Medical Institute and NIH (grant no. R01AI150297 to K.M.M.), the National Science Foundation (grant no. DGE-1745038 to P.B. and DGE-1143954 to D.A.A.), and National Cancer Institute of NIH (grant no. F31 CA228240 to D.A.A.). S.K. T.L.M. and K.M.M. designed the study. S.K. P.B. D.J.T. and T.L.M. conducted experiments related to flow cytometric analysis of immune cell populations, cell sorting and culture, and microarray, with advice from D.A.A. T.-T.L. X.H. and R.A.O. S.K. and D.J.T. performed in vitro cross-presentation assay. S.K. performed computational analysis of microarray, ChIP-seq, and ATAC-seq data with advice from D.A.A. T.T.L. K.W.O. and A.I. S.K. and T.L.M. performed all retroviral and reporter assays. T.L.M. performed EMSA. S.K. T.L.M. and K.M.M. wrote the manuscript with advice from all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "13",
doi = "10.1016/j.immuni.2020.07.018",
language = "English",
volume = "53",
pages = "759--774.e9",
journal = "Immunity",
issn = "1074-7613",
number = "4",
}