Jarid1b targets genes regulating development and is involved in neural differentiation

Biotech Research and Innovation Centre, University of Copenhagen, Denmark.
The EMBO Journal (Impact Factor: 10.75). 11/2011; 30(22):4586-600. DOI: 10.1038/emboj.2011.383
Source: PubMed

ABSTRACT H3K4 methylation is associated with active transcription and in combination with H3K27me3 thought to keep genes regulating development in a poised state. The contribution of enzymes regulating trimethylation of lysine 4 at histone 3 (H3K4me3) levels to embryonic stem cell (ESC) self-renewal and differentiation is just starting to emerge. Here, we show that the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) is dispensable for ESC self-renewal, but essential for ESC differentiation along the neural lineage. By genome-wide location analysis, we demonstrate that Jarid1b localizes predominantly to transcription start sites of genes encoding developmental regulators, of which more than half are also bound by Polycomb group proteins. Virtually all Jarid1b target genes are associated with H3K4me3 and depletion of Jarid1b in ESCs leads to a global increase of H3K4me3 levels. During neural differentiation, Jarid1b-depleted ESCs fail to efficiently silence lineage-inappropriate genes, specifically stem and germ cell genes. Our results delineate an essential role for Jarid1b-mediated transcriptional control during ESC differentiation.

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Available from: Kristian Helin, Jun 24, 2014
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    • "Additionally, the impact of arsenic on MLL expression has not been measured to date. Similarly, histone demethylase enzymes (HDM), including Jumonji-containing proteins, have been shown to be altered by toxin exposure (Chen et al., 2010); KDM5B (JARID1B), one of several histone demethylase enzymes responsible for removing methyl groups from H3K4, protects against aberrant H3K4me3 during development (Albert et al., 2013) and is involved in neuronal differentiation (Schmitz et al., 2011). Thus, we chose to assess both MLL and KDM5B expression in accordance with H3K4me3. "
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    ABSTRACT: Epidemiological studies report that arsenic exposure via drinking water adversely impacts cognitive development in children and, in adults, can lead to greater psychiatric disease susceptibility, among other conditions. While it is known that arsenic toxicity alters the epigenome, very few studies have investigated its effects on chromatin architecture in the brain. We have previously demonstrated that exposure to a low level of arsenic (50ppb) during all three trimesters of fetal/neonatal development induces deficits in adult hippocampal neurogenesis in the dentate gyrus (DG), depressive-like symptoms, and alterations in gene expression in the adult mouse brain. As epigenetic processes control these outcomes, here we assess the impact of our developmental arsenic exposure (DAE) paradigm on global histone posttranslational modifications and expression of associated chromatin-modifying proteins in the dentate gyrus and frontal cortex (FC) of adult male and female mice. DAE influenced histone 3K4 trimethylation with increased levels in the male DG and FC and decreased levels in the female DG (no change in female FC). The histone methyltransferase MLL exhibited a similar sex- and region- specific expression profile as H3K4me3 levels, while histone demethylase KDM5B expression trended in the opposite direction. DAE increased histone 3K9 acetylation levels in the male DG along with histone acetyltransferase (HAT) expression of GCN5 and decreased H3K9ac levels in the male FC along with decreased HAT expression of GCN5 and PCAF. DAE decreased expression of histone deacetylase enzymes HDAC1 and HDAC2, which were concurrent with increased H3K9ac levels but only in the female DG. Levels of H3 and H3K9me3 were not influenced by DAE in either brain region of either sex. These findings suggest that exposure to a low, environmentally relevant level of arsenic during development induces alterations in the adult brain via histone modifications and chromatin modifiers a sex- and region-specific manner. Copyright © 2015. Published by Elsevier Inc.
    Toxicology and Applied Pharmacology 07/2015; 288(1). DOI:10.1016/j.taap.2015.07.013 · 3.63 Impact Factor
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    • "ylation after inhibition of Acti - vin / Nodal signaling is consistent with the sequential H3K4me3 and H3K4me2 demethylation that is known to be mediated by this class of demethylases ( Cloos et al . 2008 ) . Interestingly , knockdown in Jarid1B expres - sion in mESCs impairs silencing of pluripotency genes and differentiation into neuroectoderm ( Schmitz et al . 2011 ) . Therefore , the epigenetic status of a core pluripo - tency network could be tightly controlled by extracellular signals through the dynamic competition of histone methylation writers and erasers ."
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    ABSTRACT: Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin-SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs. © 2015 Bertero et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 03/2015; 29(7). DOI:10.1101/gad.255984.114 · 12.64 Impact Factor
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    • "JARID1B, the H3K4me2 demethylase, has been shown to affect the expression of Oct4 and Nanog. Specifically, JARID1B plays a hand in suppressing the expression of these transcription factors as deletion allows Oct4 and Nanog expression to continue past their normal time course in an in vivo developmental model (Schmitz et al., 2011). The H3K9 demethylase JMJD1C has also shown a direct binding capacity to Oct4 (Wang et al., 2014a). "
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    ABSTRACT: Alcohol intoxicated cells broadly alter their metabolites - among them methyl and acetic acid can alter the DNA and histone epigenetic codes. Together with the promiscuous effect of alcohol on enzyme activities (including DNA methyltransferases) and the downstream effect on microRNA and transposable elements, alcohol is well placed to affect intrinsic transcriptional programs of developing cells. Considering that the developmental consequences of early alcohol exposure so profoundly affect neural systems, it is not unfounded to reason that alcohol exploits transcriptional regulators to challenge canonical gene expression and in effect, intrinsic developmental pathways to achieve widespread damage in the developing nervous system. To fully evaluate the role of epigenetic regulation in alcohol-related developmental disease, it is important to first gather the targets of epigenetic players in neurodevelopmental models. Here, we attempt to review the cellular and genomic windows of opportunity for alcohol to act on intrinsic neurodevelopmental programs. We also discuss some established targets of fetal alcohol exposure and propose pathways for future study. Overall, this review hopes to illustrate the known epigenetic program and its alterations in normal neural stem cell development and further, aims to depict how alcohol, through neuroepigenetics, may lead to neurodevelopmental deficits observed in fetal alcohol spectrum disorders.
    Frontiers in Genetics 08/2014; 5:285. DOI:10.3389/fgene.2014.00285
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