A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin States
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Authors
Bornstein, ChamutalWinter, Deborah
Barnett-Itzhaki, Zohar
David, Eyal
Kadri, Sabah
Garber, Manuel
Amit, Ido
Document Type
Journal ArticlePublication Date
2014-12-18Keywords
Amino Acids, Peptides, and ProteinsBioinformatics
Cell Biology
Computational Biology
Genetic Phenomena
Genomics
Molecular Biology
Metadata
Show full item recordAbstract
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.Source
Mol Cell. 2014 Dec 18;56(6):749-62. doi: 10.1016/j.molcel.2014.10.014. Epub 2014 Nov 20. Link to article on publisher's site
DOI
10.1016/j.molcel.2014.10.014Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31038PubMed ID
25453760Related Resources
ae974a485f413a2113503eed53cd6c53
10.1016/j.molcel.2014.10.014