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      Distinctive Chromatin in Human Sperm Packages Genes for Embryo Development

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          Summary

          As nucleosomes are widely replaced by protamine in mature human sperm, epigenetic contributions of sperm chromatin to embryo development have been considered highly limited. However, we find the retained nucleosomes significantly enriched at loci of developmental importance including imprinted gene clusters, miRNA clusters, HOX gene clusters, and the promoters of stand-alone developmental transcription and signaling factors. Importantly, histone modifications localize to particular developmental loci. H3K4me2 is enriched at certain developmental promoters, whereas large blocks of H3K4me3 localize to a subset of developmental promoters, regions in HOX clusters, certain non-coding RNAs, and generally to paternally-expressed imprinted loci, but not paternally-repressed loci. Notably, H3K27me3 is significantly enriched at developmental promoters that are repressed in early embryos, including many bivalent (H3K4me3/H3K27me3) promoters in embryonic stem cells. Finally, developmental promoters are generally DNA hypomethylated in sperm, but acquire methylation during differentiation. Taken together, epigenetic marking in sperm is extensive, and correlated with developmental regulators.

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          Most cited references 37

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          Induction of pluripotent stem cells from adult human fibroblasts by defined factors.

          Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.
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            A bivalent chromatin structure marks key developmental genes in embryonic stem cells.

            The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
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              A mammalian microRNA expression atlas based on small RNA library sequencing.

              MicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. In order to identify miRNAs and to assess their expression patterns, we sequenced over 250 small RNA libraries from 26 different organ systems and cell types of human and rodents that were enriched in neuronal as well as normal and malignant hematopoietic cells and tissues. We present expression profiles derived from clone count data and provide computational tools for their analysis. Unexpectedly, a relatively small set of miRNAs, many of which are ubiquitously expressed, account for most of the differences in miRNA profiles between cell lineages and tissues. This broad survey also provides detailed and accurate information about mature sequences, precursors, genome locations, maturation processes, inferred transcriptional units, and conservation patterns. We also propose a subclassification scheme for miRNAs for assisting future experimental and computational functional analyses.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                26 January 2010
                14 June 2009
                23 July 2009
                21 April 2010
                : 460
                : 7254
                : 473-478
                Affiliations
                [1 ] Howard Hughes Medical Institute, Department of Oncological Sciences, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112
                [2 ]IVF and Andrology Laboratories, Departments of Surgery, Obstetrics and Gynocology, and Physiology. University of Utah School of Medicine, Salt Lake City, Utah 84112
                [3 ]Research Informatics and Bioinformatics Core Facility, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112
                Author notes

                Author Contributions. B.R.C., D.T.C. and S.S.H.; overall design. D.T.C. and S.S.H.: acquisition of samples, clinical logistics, patient consenting, Institutional Review Board documents. B.R.C., S.S.H., D.A.N. and H.Z.; detailed molecular and genomics approaches. D.A.N.; data processing and array analysis. S.S.H. and D.A.N.; sequencing analysis. S.S.H.; experiments and figures. J.P.; immunoblotting and bisulphite sequencing. B.R.C. wrote the manuscript.

                Article
                hhmipa120193
                10.1038/nature08162
                2858064
                19525931
                Funding
                Funded by: Howard Hughes Medical Institute
                Award ID: ||HHMI_
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