PMID- 30796024 OWN - NLM STAT- MEDLINE DCOM- 20191227 LR - 20210202 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 133 IP - 17 DP - 2019 Apr 25 TI - Epigenetic control of early dendritic cell lineage specification by the transcription factor IRF8 in mice. PG - 1803-1813 LID - 10.1182/blood-2018-06-857789 [doi] AB - Dendritic cells (DCs), which are vital for immune responses, are derived from bone marrow hematopoietic stem cells via common DC progenitors (CDPs). DC lineage fate decisions occurring at stages much earlier than CDPs have recently been recognized, yet the mechanism remains elusive. By single-cell RNA-sequencing, in vivo cell transfer experiments, and an assay for transposase-accessible chromatin sequencing using wild-type, IRF8-GFP chimera knock-in or IRF8-knockout mice, we demonstrate that IRF8 regulates chromatin at the lymphoid-primed multipotent progenitor (LMPP) stage to induce early commitment toward DCs. A low but significant expression of IRF8, a transcription factor essential for DC and monocyte development, was initiated in a subpopulation within LMPPs. These IRF8(+) LMPPs were derived from IRF8(-) LMPPs and predominantly produced DCs, especially classical DC1s, potentially via known progenitors, such as monocyte-DC progenitors, CDPs, and preclassical DCs. IRF8(+) LMPPs did not generate significant numbers of monocytes, neutrophils, or lymphocytes. Although IRF8(-) and IRF8(+) LMPPs displayed very similar global gene expression patterns, the chromatin of enhancers near DC lineage genes was more accessible in IRF8(+) LMPPs than in IRF8(-) LMPPs, an epigenetic change dependent on IRF8. The majority of the genes epigenetically primed by IRF8 were still transcriptionally inactive at the LMPP stage, but were highly expressed in the downstream DC lineage populations such as CDPs. Therefore, early expression of the key transcription factor IRF8 changes chromatin states in otherwise multipotent progenitors, biasing their fate decision toward DCs. CI - (c) 2019 by The American Society of Hematology. FAU - Kurotaki, Daisuke AU - Kurotaki D AD - Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. FAU - Kawase, Wataru AU - Kawase W AD - Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. FAU - Sasaki, Haruka AU - Sasaki H AD - Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. FAU - Nakabayashi, Jun AU - Nakabayashi J AD - Advanced Medical Research Center, Yokohama City University, Yokohama, Japan. FAU - Nishiyama, Akira AU - Nishiyama A AD - Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. FAU - Morse, Herbert C 3rd AU - Morse HC 3rd AD - Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Rockville, MD. FAU - Ozato, Keiko AU - Ozato K AD - Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD; and. FAU - Suzuki, Yutaka AU - Suzuki Y AD - Department of Computational Biology and Medical Sciences, The University of Tokyo, Chiba, Japan. FAU - Tamura, Tomohiko AU - Tamura T AD - Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. AD - Advanced Medical Research Center, Yokohama City University, Yokohama, Japan. LA - eng PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20190222 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Interferon Regulatory Factors) RN - 0 (interferon regulatory factor-8) SB - IM CIN - Blood. 2019 Apr 25;133(17):1795-1797. PMID: 31023741 MH - Animals MH - Cell Lineage/*genetics MH - Cells, Cultured MH - Dendritic Cells/*cytology/metabolism MH - *Epigenesis, Genetic MH - Female MH - *Gene Expression Regulation MH - Interferon Regulatory Factors/*physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Multipotent Stem Cells/*cytology/metabolism MH - Precursor Cells, B-Lymphoid/*cytology/metabolism PMC - PMC6484390 COIS- Conflict-of-interest disclosure: The authors declare no competing financial interests. EDAT- 2019/02/24 06:00 MHDA- 2019/12/28 06:00 PMCR- 2020/04/25 CRDT- 2019/02/24 06:00 PHST- 2018/06/20 00:00 [received] PHST- 2019/02/13 00:00 [accepted] PHST- 2019/02/24 06:00 [pubmed] PHST- 2019/12/28 06:00 [medline] PHST- 2019/02/24 06:00 [entrez] PHST- 2020/04/25 00:00 [pmc-release] AID - S0006-4971(20)42600-X [pii] AID - 2019/857789 [pii] AID - 10.1182/blood-2018-06-857789 [doi] PST - ppublish SO - Blood. 2019 Apr 25;133(17):1803-1813. doi: 10.1182/blood-2018-06-857789. Epub 2019 Feb 22.