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      Crosstalk among Epigenetic Pathways Regulates Neurogenesis

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          The process of neurogenesis includes neural stem cell proliferation, fate specification, young neuron migration, neuronal maturation, and functional integration into existing circuits. Although neurogenesis occurs largely during embryonic development, low levels but functionally important neurogenesis persists in restricted regions of the postnatal brain, including the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone of the lateral ventricles. This review will cover both embryonic and adult neurogenesis with an emphasis on the latter. Of the many endogenous mediators of postnatal neurogenesis, epigenetic pathways, such as mediators of DNA methylation, chromatin remodeling systems, and non-coding RNA modulators, appear to play an integral role. Mounting evidence shows that such epigenetic factors form regulatory networks, which govern each step of postnatal neurogenesis. In this review, we explore the emerging roles of epigenetic mechanisms particularly microRNAs, element-1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF), polycomb proteins, and methyl-CpG bindings proteins, in regulating the entire process of postnatal and adult neurogenesis. We further summarize recent data regarding how the crosstalk among these different epigenetic proteins forms the critical regulatory network that regulates neuronal development. We finally discuss how crosstalk between these pathways may serve to translate environmental cues into control of the neurogenic process.

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          Most cited references 209

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          MicroRNAs: target recognition and regulatory functions.

           David Bartel (2009)
          MicroRNAs (miRNAs) are endogenous approximately 23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.
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            Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.

            Noncoding RNAs (ncRNA) participate in epigenetic regulation but are poorly understood. Here we characterize the transcriptional landscape of the four human HOX loci at five base pair resolution in 11 anatomic sites and identify 231 HOX ncRNAs that extend known transcribed regions by more than 30 kilobases. HOX ncRNAs are spatially expressed along developmental axes and possess unique sequence motifs, and their expression demarcates broad chromosomal domains of differential histone methylation and RNA polymerase accessibility. We identified a 2.2 kilobase ncRNA residing in the HOXC locus, termed HOTAIR, which represses transcription in trans across 40 kilobases of the HOXD locus. HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and is required for PRC2 occupancy and histone H3 lysine-27 trimethylation of HOXD locus. Thus, transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance; these results have broad implications for gene regulation in development and disease states.
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              Mammalian microRNAs predominantly act to decrease target mRNA levels

              Summary MicroRNAs (miRNAs) are endogenous ∼22-nucleotide RNAs that play important gene-regulatory roles by pairing to the mRNAs of protein-coding genes to direct their repression. Repression of these regulatory targets leads to decreased translational efficiency and/or decreased mRNA levels, but the relative contributions of these two outcomes have been largely unknown, particularly for endogenous targets expressed at low-to-moderate levels. Here, we use ribosome profiling to measure the overall effects on protein production and compare these to simultaneously measured effects on mRNA levels. For both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for most (≥84%) of the decreased protein production. These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output.

                Author and article information

                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Research Foundation
                08 May 2012
                : 6
                1simpleCellular and Molecular Biology Graduate Program, University of Wisconsin–Madison Madison, WI, USA
                2simpleWaisman Center, University of Wisconsin–Madison Madison, WI, USA
                3simpleGraduate Program in Neurobiology and Behavior, University of Washington Seattle, WA, USA
                4simpleDepartment of Neuroscience, University of Wisconsin–Madison Madison, WI, USA
                Author notes

                Edited by: Yanhong Shi, City of Hope, USA

                Reviewed by: Jenny Hsieh, University of Texas Southwestern Medical Center, USA; Ashok K. Shetty, Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, USA; Gonzalo Alvarez-Bolado, University of Heidelberg, Germany

                *Correspondence: Xinyu Zhao, Department of Neuroscience and Waisman Center, University of Wisconsin–Madison School of Medicine and Public Health, Madison, WI 53705, USA. e-mail: xzhao@

                This article was submitted to Frontiers in Neurogenesis, a specialty of Frontiers in Neuroscience.

                Copyright © 2012 Jobe, McQuate and Zhao.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                Figures: 2, Tables: 0, Equations: 0, References: 199, Pages: 15, Words: 15704
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