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

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 Krüppel-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

Developing essential professional skills: a framework for teaching and learning about feedback.

BACKGROUND: The ability to give and receive feedback effectively is a key skill for doctors, aids learning between all levels of the medical hierarchy, and provides a basis for reflective practice and life-long learning. How best to teach this skill? DISCUSSION: We suggest that a single "teaching the skill of feedback" session provides superficial and ineffective learning in a medical culture that often uses feedback skills poorly or discourages feedback. Our experience suggests that both the skill and the underlying attitude informing its application must be addressed, and is best done so longitudinally and reiteratively using different forms of feedback delivery. These feedback learning opportunities include written and oral, peer to peer and cross-hierarchy, public and private, thereby addressing different cognitive processes and attitudinal difficulties. SUMMARY: We conclude by asking whether it is possible to build a consensus approach to a framework for teaching and learning feedback skills?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

Mendel's laws of heredity on his 200th birthday : What have we learned by considering exceptions?

Peer reviewedPostprin

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

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.

Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs in trans in a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance

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

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