Abstract
Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development.
Highlights
Dendritic cells (DC) represent specialized immune cells that develop from hematopoietic stem cells [1,2]
Expressed genes were categorized in six cell-specific clusters: progenitors (MPP/common DC progenitors (CDP)), Multipotent progenitors (MPP), CDP, Pan-DC, conventional DC (cDC) and plasmacytoid DC (pDC) cluster (Figure 1B and Supplementary Table S1)
We demonstrate that consecutive changes of stage-specific expression for key DC regulators, including PU.1, Irf1, Irf8, Batf3, Spib and Tcf4, are associated with specific histone modifications in promoter and enhancer sequences
Summary
Dendritic cells (DC) represent specialized immune cells that develop from hematopoietic stem cells [1,2]. DC are widely distributed in both lymphoid and non-lymphoid tissues and bridge innate and adaptive immune responses. DC function builds on their capacity to capture, process and present antigens to T cells [1,3,4]. DC are divided into distinct subsets according to their localization, phenotype and function [1,3,4]. Lymphoid tissues contain classical/conventional DC (cDC) and plasmacytoid DC (pDC), which represent the main DC subsets. Peripheral organs contain migratory tissue DC, which capture antigens and migrate to lymphoid organs for antigen presentation to T cells
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