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Dual and separable roles for Ezh2 in neurogenic astroglia

ABSTRACT: The epigenetic mechanisms that enable specialized astrocytes to retain neurogenic competence throughout adult life are still poorly understood. Here we show that astrocytes that serve as neural stem cells (NSCs) in the adult mouse subventricular zone (SVZ) express the histone methyltransferase EZH2. This Polycomb repressive factor is required for neurogenesis independent of its role in SVZ NSC proliferation, as Ink4a/Arf-deficiency in Ezh2-deleted SVZ NSCs rescues cell proliferation, but neurogenesis remains defective. Olig2 is a direct target of EZH2, and repression of this bHLH transcription factor is critical for neuronal differentiation. Furthermore, Ezh2 prevents the inappropriate activation of genes that specify non-SVZ neuronal subtypes. In the human brain, SVZ cells including local astroglia also express EZH2, correlating with postnatal neurogenesis. Thus, EZH2 is an epigenetic regulator that distinguishes neurogenic SVZ astrocytes, orchestrating distinct and separable aspects of adult stem cell biology, which has important implications for regenerative medicine and oncogenesis. Examination of histone modifications (H3K27me3 and H3K4me3) in subventricular zone neural stem cells

ORGANISM(S): Mus musculus

SUBMITTER: Daniel Lim

PROVIDER: E-GEOD-56394 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Dual and separable roles for Ezh2 in neurogenic astroglia

Project description:The epigenetic mechanisms that enable specialized astrocytes to retain neurogenic competence throughout adult life are still poorly understood. Here we show that astrocytes that serve as neural stem cells (NSCs) in the adult mouse subventricular zone (SVZ) express the histone methyltransferase EZH2. This Polycomb repressive factor is required for neurogenesis independent of its role in SVZ NSC proliferation, as Ink4a/Arf-deficiency in Ezh2-deleted SVZ NSCs rescues cell proliferation, but neurogenesis remains defective. Olig2 is a direct target of EZH2, and repression of this bHLH transcription factor is critical for neuronal differentiation. Furthermore, Ezh2 prevents the inappropriate activation of genes that specify non-SVZ neuronal subtypes. In the human brain, SVZ cells including local astroglia also express EZH2, correlating with postnatal neurogenesis. Thus, EZH2 is an epigenetic regulator that distinguishes neurogenic SVZ astrocytes, orchestrating distinct and separable aspects of adult stem cell biology, which has important implications for regenerative medicine and oncogenesis.

2014-05-02 | GSE56394 | GEO

Timecourse analysis of Ezh2-dependent gene expression by SVZ NSCs during differentiation

Project description:Previous work had established that Ezh2-deleted neural stem cells (NSCs) from the postnatal mouse subventricular zone (SVZ) had a deficit in both proliferation and neuronal differentiation both in vivo and in vitro. Ezh2-deleted NSCs in an Ink4a/Arf-deleted background proliferated normally but still displayed a neurogenesis defect, suggesting that Ezh2 is necessary for the proper expression of genes responsible for neuronal differentiation. Our results identify genes that are differentially regulated between control and Ezh2-deleted SVZ NSCs during differentiation. Total RNA obtained from SVZ NSCs 0, 1, 2, 4, and 7 days after switching from proliferation to differentiation media.

2014-05-02 | E-GEOD-56988 | biostudies-arrayexpress

Timecourse analysis of Ezh2-dependent gene expression by SVZ NSCs during differentiation

2014-05-02 | GSE56988 | GEO

Analysis of Mll1-deficiency identifies neurogenic transcriptional modules and Brn4 as a factor for direct astrocyte-to-neuron reprogramming

Project description:BACKGROUND: Mixed lineage leukemia-1 (Mll1) epigenetically regulates gene expression patterns that specify cellular identity in both embryonic development and adult stem cell populations. In the adult mouse brain, multipotent neural stem cells (NSCs) in the subventricular zone (SVZ) generate new neurons throughout life and Mll1 is required for this postnatal neurogenesis but not for glial cell differentiation. Analysis of Mll1-dependent transcription may identify neurogenic genes useful for the direct reprogramming of astrocytes into neurons. OBJECTIVE: To identify Mll1-dependent transcriptional modules and determine whether genes in the neurogenic modules can be used to directly reprogram astrocytes into neurons. METHODS: We performed gene coexpression module analysis on microarray data from differentiating wild-type and Mll1-deleted SVZ NSCs. Key developmental regulators belonging to the neurogenic modules were overexpressed in Mll1-deleted cells and cultured cortical astrocytes, and cell phenotypes were analyzed by immunocytochemistry and electrophysiology. RESULTS: Transcriptional modules that correspond to neurogenesis were identified in wild-type NSCs. Modules related to astrocytes and oligodendrocytes were enriched in Mll1-deleted NSCs, consistent with their gliogenic potential. Overexpression of genes selected from the neurogenic modules enhanced the production of neurons from Mll1- deleted cells, and the overexpression of Brn4 (Pou3f4) in non-neurogenic cortical astroglia induced their transdifferentiation into electrophysiologically active neurons. CONCLUSIONS: Our results demonstrate that Mll1 is required for the expression of neurogenic - but not gliogenic - transcriptional modules in a multipotent NSC population and further indicate that specific Mll1-dependent genes may be useful for direct reprogramming strategies.

2016-03-06 | GSE56835 | GEO

Dnmt3a-dependent non-promoter DNA methylation facilitates transcription of neurogenic genes

Project description:This SuperSeries is composed of the following subset Series: GSE22473: Murine postnatal subventricular zone (SVZ) neural stem cells (NSCs): Wild-type (WT) vs. Dnmt3a-null (KO) GSE22474: Genome-wide location analysis of Dnmt3a-mediated epigenetic regulation in murine postnatal subventricular zone (SVZ) neural stem cells (NSCs) [Agilent] GSE22475: Genome-wide location analysis of Dnmt3a-mediated epigenetic regulation in murine postnatal subventricular zone (SVZ) neural stem cells (NSCs) [NimbleGen] Refer to individual Series

2010-06-24 | E-GEOD-22476 | biostudies-arrayexpress

Topoisomerase IIA in Adult NSCs Regulates SVZ Neurogenesis by Transcriptional Activation of Usp37 (RNA-Seq)

Project description:Topoisomerase IIA (TOP2a) has been traditionally known as an important nuclear enzyme that resolves entanglements and relieves torsional stress of DNA double strands. However, little is known about its function in genomic transcriptional regulation, especially during adult neurogenesis. Here, we show that TOP2a is preferentially expressed in neurogenic niches in the brain of adult mice, such as the subventricular zone (SVZ). Conditional knockout of Top2a in adult neural stem cells (NSCs) in the SVZ significantly inhibits their self-renewal and proliferation and ultimately reduces neurogenesis. To gain insight into the molecular mechanisms by which TOP2a regulates adult NSCs, we perform RNA-sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) and identify ubiquitin-specific proteases 37 (Usp37) as a direct TOP2a target gene. Importantly, overexpression of Usp37 is sufficient to rescue the impaired self-renewal ability of adult NSCs caused by Top2a knockdown. Taken together, our proof-of-principle study illustrates a TOP2a/Usp37-mediated novel molecular mechanism of adult neurogenesis, which will significantly expand our understanding of the function of topoisomerase in adult brain.

2022-09-20 | GSE192398 | GEO

Topoisomerase IIA in Adult NSCs Regulates SVZ Neurogenesis by Transcriptional Activation of Usp37 (ChIP-Seq)

2022-09-20 | GSE192397 | GEO

Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis

Project description:Neural stem cells (NSCs) generate new neurons throughout life in two distinct areas of the mammalian brain: the subventricular zone (SVZ) lining the lateral ventricles and the hippocampal dentate gyrus (DG). How gene expression signatures differ among NSCs and immature neurons within and between these adult neurogenic regions is unknown. We isolated NSCs and their progeny using transgenic mice expressing GFP under the control of the Sox2 promoter (labeling NSCs) and transgenic mice expressing DsRed under the control of the doublecortin (Dcx) promoter (labeling immature neurons). Comparison of the transcriptomes of SOX2+ cells derived from both neurogenic areas revealed that NSCs are highly similar but that functionally significant differences in gene expression exist: IGF2, which is expressed only in SOX2+ cells in the DG but not in the SVZ, is required for proliferation of DG-derived but not SVZ-derived NSCs. Gene expression profiles strongly diverged in immature neurons, and we provide evidence that ephrinB3, which was up-regulated only in the DG but not in the SVZ during neuronal differentiation, regulates the survival of newborn granule cells. Thus, the data provided here show that stem cell populations in the adult DG and SVZ are similar but have unique properties that manifest themselves later during neural differentiation, resulting in distinct neuronal populations Hippocampi and SVZ from 6 week old DCX-DsRed and Sox2-GFP Reporter mice were dissected and cell sorted using FACS. cDNA were generated and analysed using Agilent Platform.

2011-12-31 | E-GEOD-21208 | biostudies-arrayexpress

Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo [expression]

Project description:Long noncoding RNAs (lncRNAs) have been described in cell lines and various whole tissues, but lncRNA analysis of development in vivo is limited. Here, we comprehensively analyze lncRNA expression for the adult mouse subventricular zone neural stem cell lineage. We utilize complementary genome-wide techniques including RNA-seq, RNA CaptureSeq, and ChIP-seq to associate specific lncRNAs with neural cell types, developmental processes, and human disease states. By integrating data from chromatin state maps, custom microarrays, and FACS purification of the subventricular zone lineage, we stringently identify lncRNAs with potential roles in adult neurogenesis. shRNA-mediated knockdown of two such lncRNAs, Six3os and Dlx1as, indicate roles for lncRNAs in the glial-neuronal lineage specification of multipotent adult stem cells. Our data and workflow thus provide a uniquely coherent in vivo lncRNA analysis and form the foundation of a user-friendly online resource for the study of lncRNAs in development and disease. SVZ monolayer cultures were differentiated in vitro for 1, 2, 4 days, and gene expression changes were measured. SVZ lineage was isolated by FACS using established protocols to separate transit amplifying (TA), neuroblast (NB), activated stem cells (NSCs), and niche astrocytes (astros), and gene expression of each cell type was measured. All arrays are Nimblegen Mouse Gene Expression 12x135K Array.

2013-04-11 | E-GEOD-45280 | biostudies-arrayexpress

Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo [lncRNA Array]

Project description:Long noncoding RNAs (lncRNAs) have been described in cell lines and various whole tissues, but lncRNA analysis of development in vivo is limited. Here, we comprehensively analyze lncRNA expression for the adult mouse subventricular zone neural stem cell lineage. We utilize complementary genome-wide techniques including RNA-seq, RNA CaptureSeq, and ChIP-seq to associate specific lncRNAs with neural cell types, developmental processes, and human disease states. By integrating data from chromatin state maps, custom microarrays, and FACS purification of the subventricular zone lineage, we stringently identify lncRNAs with potential roles in adult neurogenesis. shRNA-mediated knockdown of two such lncRNAs, Six3os and Dlx1as, indicate roles for lncRNAs in the glial-neuronal lineage specification of multipotent adult stem cells. Our data and workflow thus provide a uniquely coherent in vivo lncRNA analysis and form the foundation of a user-friendly online resource for the study of lncRNAs in development and disease. SVZ monolayer cultures were differentiated in vitro for 1,2,4 days, and gene expression changes were measured. SVZ lineage was isolated by FACS using established protocols to separate transit amplifying (TA), neuroblast (NB), activated stem cells (NSCs), and niche astrocytes (astros), and gene expression of each cell type was measured. All arrays are custom lncRNA arrays.

2013-04-11 | E-GEOD-45281 | biostudies-arrayexpress

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