Stage-specific transcription factors drive astrogliogenesis by remodeling gene regulatory landscapes

TY - JOUR

T1 - Stage-specific transcription factors drive astrogliogenesis by remodeling gene regulatory landscapes

AU - Tiwari, Neha

AU - Pataskar, Abhijeet

AU - Péron, Sophie

AU - Thakurela, Sudhir

AU - Sahu, Sanjeeb Kumar

AU - Figueres-Oñate, Maria

AU - Marichal, Nicolás

AU - López-Mascaraque, Laura

AU - Tiwari, Vijay K

AU - Berninger, Benedikt

PY - 2018/10/4

Y1 - 2018/10/4

N2 - A 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.

AB - A 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.

U2 - 10.1016/j.stem.2018.09.008

DO - 10.1016/j.stem.2018.09.008

M3 - Article

SN - 1934-5909

VL - 23

SP - 557-571.e8

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -