A Negative Feedback Loop of Transcription Factors Specifies Alternative Dendritic Cell Chromatin States
Feedback, Physiological
0301 basic medicine
Bioinformatics
CCAAT-Enhancer-Binding Protein-beta
and Proteins
Computational Biology
Genomics
Cell Biology
Dendritic Cells
Chromatin
Epigenesis, Genetic
03 medical and health sciences
Enhancer Elements, Genetic
HEK293 Cells
Interferon Regulatory Factors
Humans
Amino Acids
Genetic Phenomena
Peptides
Transcriptome
Molecular Biology
Protein Binding
DOI:
10.1016/j.molcel.2014.10.014
Publication Date:
2014-11-21T00:40:43Z
AUTHORS (7)
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.
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