title: Dendritic cell development requires histone deacetylase activity.
abstract: DCs develop from multipotent progenitors (MPPs), which commit into DC-restricted common dendritic cell progenitors (CDPs). CDPs further differentiate into classical DCs (cDCs) and plasmacytoid DCs (pDCs). Here, we studied the impact of histone acetylation on DC development in C57BL/6 mice by interfering with histone acetylation and deacetylation, employing histone deacetylase (HDAC) inhibitors. We observed that commitment of MPPs into CDPs was attenuated by HDAC inhibition and that pDC development was specifically blocked. Gene expression profiling revealed that HDAC inhibition prevents establishment of a DC-specific gene expression repertoire. Importantly, protein levels of the core DC transcription factor PU.1 were reduced in HDAC inhibitor-treated cells and consequently PU.1 recruitment at PU.1 target genes Fms-like tyrosine kinase 3 (Flt3), interferon regulatory factor 8 (IRF8), and PU.1 itself was impaired. Thus, our results demonstrate that attenuation of PU.1 expression by HDAC inhibition causes reduced expression of key DC regulators, which results in attenuation of DC development. We propose that chromatin modifiers, such as HDACs, are required for establishing a DC gene network, where Flt3/STAT3 signaling drives PU.1 and IRF8 expression and DC development. Taken together, our study identifies HDACs as critical regulators of DC lineage commitment and development.
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Chauvistré
authors.forename: Caroline
authors.initials: C
authors.lastname: Küstermann
authors.forename: Nina
authors.initials: N
authors.lastname: Rehage
authors.forename: Theresa
authors.initials: T
authors.lastname: Klisch
authors.forename: Saskia
authors.initials: S
authors.lastname: Mitzka
authors.forename: Piritta
authors.initials: P
authors.lastname: Felker
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Seré
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D002843:Chromatin; D006655:Histone Deacetylases; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D051941:fms-Like Tyrosine Kinase 3; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; C494087:Stat3 protein, mouse; C497971:Flt3 protein, mouse
keywords: Dendritic cells; Flt3; HDAC; Histone acetylation; PU.1