Journal
MOLECULAR CELL
Volume 56, Issue 6, Pages 749-762Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2014.10.014
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Funding
- European Research Council [309788]
- Israeli Science Foundation [1782/11]
- Human Frontiers Science Program
- Center for Excellence in Genome Science from NHGRI [1P50HG006193]
- Azrieli Foundation
- European Research Council (ERC) [309788] Funding Source: European Research Council (ERC)
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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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