A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin States
Program in Bioinformatics and Integrative Biology; Garber Lab
Amino Acids, Peptides, and Proteins | Bioinformatics | Cell Biology | Computational Biology | Genetic Phenomena | Genomics | Molecular Biology
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.
DOI of Published Version
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
Bornstein, Chamutal; Winter, Deborah; Barnett-Itzhaki, Zohar; David, Eyal; Kadri, Sabah; Garber, Manuel; and Amit, Ido, "A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin States" (2014). Garber Lab Publications. 6.