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
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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