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Stage-Specific Transcription Factors Drive Astrogliogenesis by Remodeling Gene Regulatory Landscapes.

ABSTRACT: 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.

SUBMITTER: Tiwari N

PROVIDER: S-EPMC6179960 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Stage-Specific Transcription Factors Drive Astrogliogenesis by Remodeling Gene Regulatory Landscapes.

Tiwari Neha N Pataskar Abhijeet A Péron Sophie S Thakurela Sudhir S Sahu Sanjeeb Kumar SK Figueres-Oñate María M Marichal Nicolás N López-Mascaraque Laura L Tiwari Vijay K VK Berninger Benedikt B

Cell stem cell 20181001 4

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 prime ...[more]

PMID: 30290178

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Project description:The gene regulatory mechanisms that steer neural stem cells towards astrocytes during brain development are largely unknown. Here we set out to comprehensively identify transcription factors that drive the developmental trajectory of astrogliogenesis from mouse embryonic stem cells. To attain this we performed a genomewide analysis of gene expression and epigenetic signature hallmarks of primed and active enhancers through the distinct stages of astrogliogenesis. We revealed distal regulatory elements that become activated in a stage-specific manner which confer the transcriptional program underlying generation and maturation of astrocytes. By searching for lineage-specific transcription factors functioning at these elements, we identified ATF3 and NFIA as drivers of differentiation of neural precursor cells to astrocytes, while RUNX2 promotes their maturation. These transcription factors are crucial for switching the chromatin state of these elements from primed to active, thereby driving the gene expression program underlying astrocyte differentiation and maturation.Method: RNA was extracted from embryonic stem cells (ES) differentiated into neural progenitor cells (aNPC) and subsequently differentiated for 1 day into early astrocytes (eA) and further progressively for 5 and 21 days into mature astrocytes (lA_1 and lA_2). These samples are further subjected for RNA-sequencing to reveal the genome wide changes at transcriptional level at each stage. aNPC, eA and lA_1 (further called as lA) were subjected for H3K27ac and H3K4me1 ChIP and sequenced genome wide (ChIP-seq) to reveal the active and primed enhancers regions during astrogliogenesis, respectively. In quest to identify the TF required for early and late astrogliogeneis, we depleted Nfia (SiNfia) and Atf3 (siAtf3) in eA and Stat3 (siStat3), Prdm9 (siPrdm9) and Runx2 (siRunx2) at lA by using siRNAs and perfomed H3K27ac ChIP and sequence them. We also extracted RNA after depletion (only after siNfia, siAtf3 and siRunx2) and perform the RNA-seq.

Project description:BackgroundFew somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear.MethodsTo identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers.ResultsOur integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2. Using ATAC-seq, we identified a metastasis open-chromatin signature that is elevated in basal-like and HER2-enriched breast cancer subtypes and associates with worse prognosis in human samples. We further uncovered TFs associated with the open chromatin landscapes of metastatic cells and whose expression correlates with risk for metastasis. While some of these TFs are associated with primary breast tumor subtypes, others more specifically correlate with lung or brain metastasis.ConclusionsWe identify distinctive epigenomic properties of breast cancer cells that metastasize to the lung and brain. We also demonstrate that signatures of active chromatin sites are partially linked to human breast cancer subtypes with poor prognosis, and that specific TFs can independently distinguish lung and brain relapse.

Dataset Information

Stage-Specific Transcription Factors Drive Astrogliogenesis by Remodeling Gene Regulatory Landscapes.

Publications

Stage-Specific Transcription Factors Drive Astrogliogenesis by Remodeling Gene Regulatory Landscapes.

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