1,900 research outputs found
Distinguishing epigenetic marks of developmental and imprinting regulation.
BACKGROUND: The field of epigenetics is developing rapidly, however we are only beginning to comprehend the complexity of its influence on gene regulation. Using genomic imprinting as a model we examine epigenetic profiles associated with different forms of gene regulation. Imprinting refers to the expression of a gene from only one of the chromosome homologues in a parental-origin-specific manner. This is dependent on heritable germline epigenetic control at a cis-acting imprinting control region that influences local epigenetic states. Epigenetic modifications associated with imprinting regulation can be compared to those associated with the more canonical developmental regulation, important for processes such as differentiation and tissue specificity. Here we test the hypothesis that these two mechanisms are associated with different histone modification enrichment patterns. RESULTS: Using high-throughput data extraction with subsequent analysis, we have found that particular histone modifications are more likely to be associated with either imprinting repression or developmental repression of imprinted genes. H3K9me3 and H4K20me3 are together enriched at imprinted genes with differentially methylated promoters and do not show a correlation with developmental regulation. H3K27me3 and H3K4me3, however, are more often associated with developmental regulation. We find that imprinted genes are subject to developmental regulation through bivalency with H3K4me3 and H3K27me3 enrichment on the same allele. Furthermore, a specific tri-mark signature comprising H3K4me3, H3K9me3 and H4K20me3 has been identified at all imprinting control regions. CONCLUSION: A large amount of data is produced from whole-genome expression and epigenetic profiling studies of cellular material. We have shown that such publicly available data can be mined and analysed in order to generate novel findings for categories of genes or regulatory elements. Comparing two types of gene regulation, imprinting and developmental, our results suggest that different histone modifications associate with these distinct processes. This form of analysis is therefore a useful tool to elucidate the complex epigenetic code associated with genome function and to determine the underlying features conferring epigenetic states.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are
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Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans -Acting Modifiers
Approximately 10 percent of the mouse genome consists of endogenous retroviruses (ERVs), relics of ancient retroviral infections that are classified based on their relatedness to exogenous retroviral genera. Because of the ability of ERVs to retrotranspose, as well as their cis-acting regulatory potential due to functional elements located within the elements, mammalian ERVs are generally subject to epigenetic silencing by DNA methylation and repressive histone modifications. The mobilisation and expansion of ERV elements is strain-specific, leading to ERVs being highly polymorphic between inbred mouse strains, hinting at the possibility of the strain-specific regulation of ERVs. In this review, we describe the existing evidence of mouse strain-specific epigenetic control of ERVs and discuss the implications of differential ERV regulation on epigenetic inheritance models. We consider KrĂŒppel-associated box domain (KRAB) zinc finger proteins as likely candidates for strain-specific ERV modifiers, drawing on insights gained from the study of the strain-specific behaviour of transgenes. We conclude by considering the coevolution of KRAB zinc finger proteins and actively transposing ERV elements, and highlight the importance of cross-strain studies in elucidating the mechanisms and consequences of strain-specific ERV regulation
Mendel's laws of heredity on his 200th birthday : What have we learned by considering exceptions?
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Epigenetic Mechanisms of ART-Related Imprinting Disorders: Lessons From iPSC and Mouse Models.
The rising frequency of ART-conceived births is accompanied by the need for an improved understanding of the implications of ART on gametes and embryos. Increasing evidence from mouse models and human epidemiological data suggests that ART procedures may play a role in the pathophysiology of certain imprinting disorders (IDs), including Beckwith-Wiedemann syndrome, Silver-Russell syndrome, Prader-Willi syndrome, and Angelman syndrome. The underlying molecular basis of this association, however, requires further elucidation. In this review, we discuss the epigenetic and imprinting alterations of in vivo mouse models and human iPSC models of ART. Mouse models have demonstrated aberrant regulation of imprinted genes involved with ART-related IDs. In the past decade, iPSC technology has provided a platform for patient-specific cellular models of culture-associated perturbed imprinting. However, despite ongoing efforts, a deeper understanding of the susceptibility of iPSCs to epigenetic perturbation is required if they are to be reliably used for modelling ART-associated IDs. Comparing the patterns of susceptibility of imprinted genes in mouse models and IPSCs in culture improves the current understanding of the underlying mechanisms of ART-linked IDs with implications for our understanding of the influence of environmental factors such as culture and hormone treatments on epigenetically important regions of the genome such as imprints
The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila
<p>Abstract</p> <p>Background</p> <p>Mammalian <it>Delta-like 1 </it>(<it>Dlk-1</it>) protein shares homology with Notch ligands but lacks a critical receptor-binding domain. Thus it is unclear whether it is able to interact with Notch <it>in vivo</it>. Unlike mammals, <it>Drosophila </it>have a single Notch receptor allowing a simple <it>in vivo </it>assay for mammalian <it>Dlk1 </it>function.</p> <p>Results</p> <p>Here we show that membrane-bound DLK1 can regulate Notch leading to altered cellular distribution of Notch itself and inhibiting expression of Notch target genes. The resulting adult phenotypes are indicative of reduced Notch function and are enhanced by <it>Notch </it>mutations, confirming that DLK1 action is antagonistic. In addition, cells expressing an alternative <it>Dlk1 </it>isoform exhibit alterations in cell size, functions previously not attributed to Notch suggesting that DLK1 might also act via an alternative target.</p> <p>Conclusion</p> <p>Our results demonstrate that DLK1 can regulate the Notch receptor despite its atypical structure.</p
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The evolution of imprinting: chromosomal mapping of orthologues of mammalian imprinted domains in monotreme and marsupial mammals.
BACKGROUND: The evolution of genomic imprinting, the parental-origin specific expression of genes, is the subject of much debate. There are several theories to account for how the mechanism evolved including the hypothesis that it was driven by the evolution of X-inactivation, or that it arose from an ancestrally imprinted chromosome. RESULTS: Here we demonstrate that mammalian orthologues of imprinted genes are dispersed amongst autosomes in both monotreme and marsupial karyotypes. CONCLUSION: These data, along with the similar distribution seen in birds, suggest that imprinted genes were not located on an ancestrally imprinted chromosome or associated with a sex chromosome. Our results suggest imprinting evolution was a stepwise, adaptive process, with each gene/cluster independently becoming imprinted as the need arose.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are
Germline and somatic imprinting in the nonhuman primate highlights species differences in oocyte methylation.
Genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. Defects in normal imprinting are found in cancer, assisted reproductive technologies, and several human syndromes. In mouse models, germline-derived DNA methylation is shown to regulate imprinting. Though imprinting is largely conserved between mammals, species- and tissue-specific domains of imprinted expression exist. Using the cynomolgus macaque (Macaca fascicularis) to assess primate-specific imprinting, we present a comprehensive view of tissue-specific imprinted expression and DNA methylation at established imprinted gene clusters. For example, like mouse and unlike human, macaque IGF2R is consistently imprinted, and the PLAGL1, INPP5F transcript variant 2, and PEG3 imprinting control regions are not methylated in the macaque germline but acquire this post-fertilization. Methylome data from human early embryos appear to support this finding. These suggest fundamental differences in imprinting control mechanisms between primate species and rodents at some imprinted domains, with implications for our understanding of the epigenetic programming process in humans and its influence on disease.This study was conducted by all authors while at the Singapore
Institute for Clinical Research and was fully supported by funding
from the Agency for Science, Technology and Research, Singapore.This is the author accepted manuscript. The final version is available from Cold Spring Harbor Laboratory Press at http://genome.cshlp.org/content/early/2015/04/10/gr.183301.114.abstract
Maintenance of Paternal Methylation and Repression of the Imprinted H19 Gene Requires MBD3
Paternal repression of the imprinted H19 gene is mediated by a differentially methylated domain (DMD) that is essential to imprinting of both H19 and the linked and oppositely imprinted Igf2 gene. The mechanisms by which paternal-specific methylation of the DMD survive the period of genome-wide demethylation in the early embryo and are subsequently used to govern imprinted expression are not known. Methyl-CpG binding (MBD) proteins are likely candidates to explain how these DMDs are recognized to silence the locus, because they preferentially bind methylated DNA and recruit repression complexes with histone deacetylase activity. MBD RNA and protein are found in preimplantation embryos, and chromatin immunoprecipitation shows that MBD3 is bound to the H19 DMD. To test a role for MBDs in imprinting, two independent RNAi-based strategies were used to deplete MBD3 in early mouse embryos, with the same results. In RNAi-treated blastocysts, paternal H19 expression was activated, supporting the hypothesis that MBD3, which is also a member of the Mi-2/NuRD complex, is required to repress the paternal H19 allele. RNAi-treated blastocysts also have reduced levels of the Mi-2/NuRD complex protein MTA-2, which suggests a role for the Mi-2/NuRD repressive complex in paternal-specific silencing at the H19 locus. Furthermore, DNA methylation was reduced at the H19 DMD when MBD3 protein was depleted. In contrast, expression and DNA methylation were not disrupted in preimplantation embryos for other imprinted genes. These results demonstrate new roles for MBD3 in maintaining imprinting control region DNA methylation and silencing the paternal H19 allele. Finally, MBD3-depleted preimplantation embryos have reduced cell numbers, suggesting a role for MBD3 in cell division
TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn.
Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N (Snrpn), contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3
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