title: A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin States.
abstract: During hematopoiesis, cells originating from the same stem cell reservoir differentiate into distinct cell types. The mechanisms enabling common progenitors to differentiate into alternative cell fates are not fully understood. Here, we identify cell-fate-determining transcription factors (TFs) governing dendritic cell (DC) development by annotating the enhancer landscapes of the DC lineage. Combining these analyses with detailed overexpression, knockdown, and ChIP-Seq studies, we show that Irf8 functions as a plasmacytoid DC epigenetic and fate-determining TF, regulating massive, cell-specific chromatin changes in thousands of pDC enhancers. Importantly, Irf8 forms a negative feedback loop with Cebpb, a monocyte-derived DC epigenetic fate-determining TF. We show that using this circuit logic, a pulse of TF expression can stably define epigenetic and transcriptional states, regardless of the microenvironment. More broadly, our study proposes a general paradigm that allows closely related cells with a similar set of signal-dependent factors to generate differential and persistent enhancer landscapes.
authors.affiliation: Department of Immunology, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Chamutal
authors.initials: C
authors.lastname: Bornstein
authors.affiliation: Department of Immunology, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Deborah
authors.initials: D
authors.lastname: Winter
authors.affiliation: Department of Immunology, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Barnett-Itzhaki
authors.affiliation: Department of Immunology, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: David
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Sabah
authors.initials: S
authors.lastname: Kadri
authors.affiliation: Program in Bioinformatics and Integrative Biology and Program in Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Garber
authors.affiliation: Department of Immunology, Weizmann Institute, Rehovot 76100, Israel. Electronic address: ido.amit@weizmann.ac.il.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D002843:Chromatin / Q000502:physiology*; D003713:Dendritic Cells / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000502:physiology*; D011485:Protein Binding; D059467:Transcriptome; D000099185:Interferon Regulatory Factor-8
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D002843:Chromatin; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; C545012:CEBPB protein, human