Abstract
SummaryA broad molecular framework of how neural stem cells are specified toward astrocyte fate during brain development has proven elusive. Here we perform comprehensive and integrated transcriptomic and epigenomic analyses to delineate gene regulatory programs that drive the developmental trajectory from mouse embryonic stem cells to astrocytes. We report molecularly distinct phases of astrogliogenesis that exhibit stage- and lineage-specific transcriptomic and epigenetic signatures with unique primed and active chromatin regions, thereby revealing regulatory elements and transcriptional programs underlying astrocyte generation and maturation. By searching for transcription factors that function at these elements, we identified NFIA and ATF3 as drivers of astrocyte differentiation from neural precursor cells while RUNX2 promotes astrocyte maturation. These transcription factors facilitate stage-specific gene expression programs by switching the chromatin state of their target regulatory elements from primed to active. Altogether, these findings provide integrated insights into the genetic and epigenetic mechanisms steering the trajectory of astrogliogenesis.
Highlights
A comprehensive understanding of the molecular mechanisms underlying cellular diversity and cell-fate specification duringCNS development remains elusive
Distinct Gene Expression and Epigenetic Landscape Define Stages of Astrogliogenesis To investigate the gene regulatory mechanism underlying astrogliogenesis, we first adapted an experimental model that uses mouse embryonic stem cells (ESCs) to generate highly enriched astrogliogenic neural precursor cells that subsequently differentiate into astrocytes (Figure 1A; Figure S1A) (Conti et al, 2005; Pollard et al, 2006). qRT-PCR and immunoblot analyses showed that these astrocytes express established markers (e.g., Gfap, S100b, Nfia, Glast, Aqp4, and Cx43) (Figures S1B and S1C; Figure 1A)
The differentiation of astrogliogenic neural precursor cells (aNPCs) into astrocytes was accompanied by a cessation of cell proliferation (Figure S1E)
Summary
A comprehensive understanding of the molecular mechanisms underlying cellular diversity and cell-fate specification duringCNS development remains elusive. Astrocytes are involved in various functions that are important for the establishment, maintenance, and plasticity of the brain (Tiwari and Berninger, 2017) Because of these important roles, malfunctions in astrocytes have been implicated in many neurological diseases (Molofsky et al, 2012). Despite these advances, the gene regulatory mechanisms that control the differentiation and maturation of astrocytes from NPCs, hereafter referred to as astrogliogenesis, remain to be uncovered. NOTCH signaling induces the expression of Nfia in neural progenitor cells, which targets the promoters of astrocyte-specific genes and causes DNA demethylation at these promoters by displacing DNMT1 (Namihira et al, 2009). At the onset of gliogenesis, the Polycomb group (PcG) proteins repress
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