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      Comparison of epigenetic mediator expression and function in mouse and human embryonic blastomeres

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          Abstract

          A map of human embryo development that combines imaging, molecular, genetic and epigenetic data for comparisons to other species and across pathologies would be greatly beneficial for basic science and clinical applications. Here, we compared mRNA and protein expression of key mediators of DNA methylation and histone modifications between mouse and human embryos, embryos from fertile/infertile couples, and following growth factor supplementation. We observed that individual mouse and human embryos are characterized by similarities and distinct differences in DNA methylation and histone modification patterns especially at the single-cell level. In particular, while mouse embryos first exhibited sub-compartmentalization of different histone modifications between blastomeres at the morula stage and cell sub-populations in blastocysts, differential histone modification expression was detected between blastomeres earlier in human embryos at the four- to eight-cell stage. Likewise, differences in epigenetic mediator expression were also observed between embryos from fertile and infertile couples, which were largely equalized in response to growth factor supplementation, suggesting that select growth factors might prevent alterations in epigenetic profiles during prolonged embryo culture. Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy generation. Taken together, data document differences in epigenetic patterns between species with implications for fertility and suggest functional roles for individual epigenetic factors during pre-implantation development.

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          Most cited references61

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          Stability and flexibility of epigenetic gene regulation in mammalian development.

          Wolf Reik (2007)
          During development, cells start in a pluripotent state, from which they can differentiate into many cell types, and progressively develop a narrower potential. Their gene-expression programmes become more defined, restricted and, potentially, 'locked in'. Pluripotent stem cells express genes that encode a set of core transcription factors, while genes that are required later in development are repressed by histone marks, which confer short-term, and therefore flexible, epigenetic silencing. By contrast, the methylation of DNA confers long-term epigenetic silencing of particular sequences--transposons, imprinted genes and pluripotency-associated genes--in somatic cells. Long-term silencing can be reprogrammed by demethylation of DNA, and this process might involve DNA repair. It is not known whether any of the epigenetic marks has a primary role in determining cell and lineage commitment during development.
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            Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.

            CpG methylation in vertebrates correlates with alterations in chromatin structure and gene silencing. Differences in DNA-methylation status are associated with imprinting phenomena and carcinogenesis. In Xenopus laevis oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array. Methylated DNA assembled into chromatin binds the transcriptional repressor MeCP2 which cofractionates with Sin3 and histone deacetylase. Silencing conferred by MeCP2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodelling of chromatin and transcriptional activation. These results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.
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              Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing.

              Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7 out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos.
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                Author and article information

                Journal
                Hum Mol Genet
                Hum. Mol. Genet
                hmg
                hmg
                Human Molecular Genetics
                Oxford University Press
                0964-6906
                1460-2083
                15 September 2014
                12 May 2014
                12 May 2014
                : 23
                : 18
                : 4970-4984
                Affiliations
                [1 ]Center for Reproductive and Stem Cell Biology, Institute for Stem Cell Biology and Regenerative Medicine,
                [2 ]Department of Obstetrics and Gynecology and
                [3 ]Department of Genetics, Stanford University School of Medicine , Stanford, CA 94305, USA
                [4 ]Reproductive Medicine Center, University of Minnesota , Minneapolis, MN 55414, USA
                [5 ]Iviomics , Valencia, Spain
                Author notes
                [* ]To whom correspondence should be addressed at: Stanford University, Institute for Stem Cell Biology and Regenerative Medicine, 265 Campus Drive West; Room 3021A, Stanford, CA 94305-5463, USA. Tel: +1 6507253803; Fax: +1 6507233825; Email: reneer@ 123456stanford.edu
                [†]

                Present address: Division of Reproductive & Developmental Sciences; Oregon National Primate Research Center and Oregon Health & Science University, Beaverton, OR 97006, USA.

                Article
                ddu212
                10.1093/hmg/ddu212
                4140471
                24821703
                f496424f-ccac-4ac1-9763-928a9f23e7f0
                © The Author 2014. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 31 January 2014
                : 15 April 2014
                : 05 May 2014
                Categories
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                Genetics
                Genetics

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