title: Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks.
abstract: Langerhans cells (LCs) are the unique dendritic cells found in the epidermis. While a great deal of attention has focused on defining the developmental origins of LCs, reports addressing the transcriptional network ruling their differentiation remain sparse. We addressed the function of a group of key DC transcription factors-PU.1, ID2, IRF4, and IRF8-in the establishment of the LC network. We show that although steady-state LC homeostasis depends on PU.1 and ID2, the latter is dispensable for bone marrow-derived LCs. PU.1 controls LC differentiation by regulating the expression of the critical TGF-β responsive transcription factor RUNX3. PU.1 directly binds to the Runx3 regulatory elements in a TGF-β-dependent manner, whereas ectopic expression of RUNX3 rescued LC differentiation in the absence of PU.1 and promoted LC differentiation from PU.1-sufficient progenitors. These findings highlight the dual molecular network underlying LC differentiation, and show the central role of PU.1 in these processes.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Michaël
authors.initials: M
authors.lastname: Chopin
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chevrier
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007249:Inflammation; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007801:Langerhans Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
chemical_list: D051797:Inhibitor of Differentiation Protein 2; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C497452:Idb2 protein, mouse