TY - JOUR
T1 - A Negative Feedback Loop of Transcription Factors Specifies Alternative Dendritic Cell Chromatin States
AU - Bornstein, Chamutal
AU - Winter, Deborah
AU - Barnett-Itzhaki, Zohar
AU - David, Eyal
AU - Kadri, Sabah
AU - Garber, Manuel
AU - Amit, Ido
N1 - Funding Information:
We wish to thank Steffen Jung, Nir Friedman, and members of the Amit labs for discussions. We thank Genia Brodsky for artwork and Itay Ovits for statistical advice. Research in the I.A. lab is supported by a grant from the European Research Council (309788) and the Israeli Science Foundation (1782/11). This work was also supported by the Human Frontiers Science Program, Career Development Award, and by the Center for Excellence in Genome Science from the NHGRI 1P50HG006193. D.W. is grateful to the Azrieli Foundation for the award of an Azrieli Fellowship.
PY - 2014/12/18
Y1 - 2014/12/18
N2 - 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.
AB - 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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U2 - 10.1016/j.molcel.2014.10.014
DO - 10.1016/j.molcel.2014.10.014
M3 - Article
C2 - 25453760
AN - SCOPUS:84918783058
VL - 56
SP - 749
EP - 762
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -