A Negative Feedback Loop of Transcription Factors Specifies Alternative Dendritic Cell Chromatin States

Chamutal Bornstein, Deborah Winter, Zohar Barnett-Itzhaki, Eyal David, Sabah Kadri, Manuel Garber, Ido Amit*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)749-762
Number of pages14
JournalMolecular cell
Volume56
Issue number6
DOIs
StatePublished - Dec 18 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'A Negative Feedback Loop of Transcription Factors Specifies Alternative Dendritic Cell Chromatin States'. Together they form a unique fingerprint.

Cite this