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  • 1
    Language: English
    In: Nature reviews. Molecular cell biology, 2018-04, Vol.19 (4), p.229-244
    Description: Heterochromatin is a key architectural feature of eukaryotic chromosomes, which endows particular genomic domains with specific functional properties. The capacity of heterochromatin to restrain the activity of mobile elements, isolate DNA repair in repetitive regions and ensure accurate chromosome segregation is crucial for maintaining genomic stability. Nucleosomes at heterochromatin regions display histone post-translational modifications that contribute to developmental regulation by restricting lineage-specific gene expression. The mechanisms of heterochromatin establishment and of heterochromatin maintenance are separable and involve the ability of sequence-specific factors bound to nascent transcripts to recruit chromatin-modifying enzymes. Heterochromatin can spread along the chromatin from nucleation sites. The propensity of heterochromatin to promote its own spreading and inheritance is counteracted by inhibitory factors. Because of its importance for chromosome function, heterochromatin has key roles in the pathogenesis of various human diseases. In this Review, we discuss conserved principles of heterochromatin formation and function using selected examples from studies of a range of eukaryotes, from yeast to human, with an emphasis on insights obtained from unicellular model organisms.
    Subject(s): Aging, Premature - genetics ; Animals ; Cell Differentiation - genetics ; Cell research ; Chromatin ; Chromatin Assembly and Disassembly - genetics ; Chromatin Assembly and Disassembly - physiology ; Chromosomes ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; DNA Repair ; Epigenesis, Genetic ; Eukaryotes ; Gene expression ; Gene Silencing ; Heredity ; Heterochromatin ; Heterochromatin - genetics ; Heterochromatin - metabolism ; Humans ; Models ; Models, Biological ; Nucleosomes ; Obesity - genetics ; Pathogenesis ; Post-translation ; Properties ; RNA, Fungal - genetics ; RNA, Fungal - metabolism ; RNA, Untranslated - genetics ; RNA, Untranslated - metabolism ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae - metabolism ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Virus Latency - genetics ; Yeast
    ISSN: 1471-0072
    E-ISSN: 1471-0080
    Source: Nature Reviews
    Source: Get It Now
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  • 2
    Language: English
    In: Nature reviews. Genetics, 2008-12, Vol.9 (12), p.923-937
    Description: The assembly of just a single kinetochore at the centromere of each sister chromatid is essential for accurate chromosome segregation during cell division. Surprisingly, despite their vital function, centromeres show considerable plasticity with respect to their chromosomal locations and activity. The establishment and maintenance of centromeric chromatin, and therefore the location of kinetochores, is epigenetically regulated. The histone H3 variant CENP-A is the key determinant of centromere identity and kinetochore assembly. Recent studies have identified many factors that affect CENP-A localization, but their precise roles in this process are unknown. We build on these advances and on new information about the timing of CENP-A assembly during the cell cycle to propose new models for how centromeric chromatin is established and propagated.
    Subject(s): Animals ; Cell Cycle - physiology ; Cell division ; Centromere - physiology ; Centromere - ultrastructure ; Centromeres ; Chromatin ; Chromatin - genetics ; Chromatin - physiology ; Chromosome Segregation - physiology ; Epigenesis, Genetic ; Genetic aspects ; Histones - genetics ; Histones - physiology ; Humans ; Kinetochores - physiology ; Kinetochores - ultrastructure ; Nucleosomes - metabolism ; Nucleosomes - ultrastructure ; Physiological aspects ; Research ; Review
    ISSN: 1471-0056
    E-ISSN: 1471-0064
    Source: Academic Search Ultimate
    Source: Nature Journals Online
    Source: Nature Reviews
    Source: Get It Now
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  • 3
    Language: English
    In: Science (American Association for the Advancement of Science), 2015-04-03, Vol.348 (6230), p.132-135
    Description: Posttranslational histone modifications are believed to allow the epigenetic transmission of distinct chromatin states, independently of associated DNA sequences. Histone H3 lysine 9 (H3K9) methylation is essential for heterochromatin formation; however, a demonstration of its epigenetic heritability is lacking. Fission yeast has a single H3K9 methyltransferase, Clr4, that directs all H3K9 methylation and heterochromatin. Using releasable tethered Clr4 reveals that an active process rapidly erases H3K9 methylation from tethering sites in wild-type cells. However, inactivation of the putative histone demethylase Epe1 allows H3K9 methylation and silent chromatin maintenance at the tethering site through many mitotic divisions, and transgenerationally through meiosis, after release of tethered Clr4. Thus, H3K9 methylation is a heritable epigenetic mark whose transmission is usually countered by its active removal, which prevents the unauthorized inheritance of heterochromatin.
    Subject(s): Deoxyribonucleic acid ; DNA ; Epigenetic inheritance ; Fission ; Genetics ; Histones ; Identification and classification ; Lysine ; Methylation ; Physiological aspects ; REPORTS ; Repositories ; Ribonucleic acid ; RNA ; Schizosaccharomyces pombe ; Tethering ; Yeast
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: JSTOR Life Sciences
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 4
    Language: English
    In: Cold Spring Harbor perspectives in biology, 2015-07-01, Vol.7 (7), p.a018770-a018770
    Description: This article discusses the advances made in epigenetic research using the model organism fission yeast Schizosaccharomyces pombe. S. pombe has been used for epigenetic research since the discovery of position effect variegation (PEV). This is a phenomenon in which a transgene inserted within heterochromatin is variably expressed, but can be stably inherited in subsequent cell generations. PEV occurs at centromeres, telomeres, ribosomal DNA (rDNA) loci, and mating-type regions of S. pombe chromosomes. Heterochromatin assembly in these regions requires enzymes that modify histones and the RNA interference (RNAi) machinery. One of the key histone-modifying enzymes is the lysine methyltransferase Clr4, which methylates histone H3 on lysine 9 (H3K9), a classic hallmark of heterochromatin. The kinetochore is assembled on specialized chromatin in which histone H3 is replaced by the variant CENP-A. Studies in fission yeast have contributed to our understanding of the establishment and maintenance of CENP-A chromatin and the epigenetic activation and inactivation of centromeres.
    Subject(s): 090 ; Autoantigens ; Centromere Protein A ; Chromatin - metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone ; CONCEPTS ; Epigenesis, Genetic ; Heterochromatin - metabolism ; Histones - metabolism ; Medicin och hälsovetenskap ; Models, Genetic ; Nucleosomes - metabolism ; RNA Interference ; RNA Polymerase II - physiology ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - metabolism
    ISSN: 1943-0264
    E-ISSN: 1943-0264
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: SWEPUB Freely available online
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  • 5
    Language: English
    In: Nature genetics, 2019-01-01, Vol.51 (1), p.96-105
    Description: DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a(W326R) pluripotent cells in vitro, and is also evident in Dnmt3a(W326R/+) dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.
    Subject(s): Animals ; Bioinformatics ; Cell cycle ; Cell Line, Tumor ; Cells, Cultured ; Deoxyribonucleic acid ; Depletion ; DNA ; DNA (Cytosine-5-)-Methyltransferases - genetics ; DNA methylation ; DNA Methylation - genetics ; DNA methyltransferase ; DNA Methyltransferase 3A ; DNA Modification Methylases - genetics ; Domains ; Dwarfism ; Dwarfism - genetics ; Female ; Fibroblasts ; Gain of Function Mutation - genetics ; Gene expression ; Gene mutations ; Genetics & Heredity ; Genomes ; HeLa Cells ; Histones - genetics ; Humans ; Life Sciences & Biomedicine ; Male ; Methylation ; Mice ; Mice, Transgenic - genetics ; Microcephaly - genetics ; Microencephaly ; Missense mutation ; Mutation ; Patients ; Peptides ; Pluripotency ; Polycomb group proteins ; Polycomb-Group Proteins - genetics ; Protein Binding - genetics ; Proteins ; Regulators ; Regulatory Sequences, Nucleic Acid - genetics ; Research ; Science & Technology ; Stem cells
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Nature communications, 2014-11-27, Vol.5 (1), p.5576-5576
    Description: Most long non-coding RNAs (lncRNAs) encoded by eukaryotic genomes remain uncharacterized. Here we focus on a set of intergenic lncRNAs in fission yeast. Deleting one of these lncRNAs exhibited a clear phenotype: drug sensitivity. Detailed analyses of the affected locus revealed that transcription of the nc-tgp1 lncRNA regulates drug tolerance by repressing the adjacent phosphate-responsive permease gene transporter for glycerophosphodiester 1 (tgp1(+)). We demonstrate that the act of transcribing nc-tgp1 over the tgp1(+) promoter increases nucleosome density, prevents transcription factor access and thus represses tgp1(+) without the need for RNA interference or heterochromatin components. We therefore conclude that tgp1(+) is regulated by transcriptional interference. Accordingly, decreased nc-tgp1 transcription permits tgp1(+) expression upon phosphate starvation. Furthermore, nc-tgp1 loss induces tgp1(+) even in repressive conditions. Notably, drug sensitivity results directly from tgp1(+) expression in the absence of the nc-tgp1 RNA. Thus, transcription of an lncRNA governs drug tolerance in fission yeast.
    Subject(s): Antifungal Agents - pharmacology ; Drug Resistance, Fungal ; Membrane Transport Proteins - genetics ; Membrane Transport Proteins - metabolism ; RNA Interference ; RNA, Fungal - genetics ; RNA, Fungal - metabolism ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; Schizosaccharomyces - drug effects ; Schizosaccharomyces - enzymology ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Transcription, Genetic
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: Nature communications, 2019-05-28, Vol.10 (1), p.2343-2343
    Description: Despite the conserved essential function of centromeres, centromeric DNA itself is not conserved. The histone-H3 variant, CENP-A, is the epigenetic mark that specifies centromere identity. Paradoxically, CENP-A normally assembles on particular sequences at specific genomic locations. To gain insight into the specification of complex centromeres, here we take an evolutionary approach, fully assembling genomes and centromeres of related fission yeasts. Centromere domain organization, but not sequence, is conserved between Schizosaccharomyces pombe, S. octosporus and S. cryophilus with a central CENP-A(Cnp1) domain flanked by heterochromatic outer-repeat regions. Conserved syntenic clusters of tRNA genes and 5S rRNA genes occur across the centromeres of S. octosporus and S. cryophilus, suggesting conserved function. Interestingly, nonhomologous centromere central-core sequences from S. octosporus and S. cryophilus are recognized in S. pombe, resulting in cross-species establishment of CENP-A(Cnp1) chromatin and functional kinetochores. Therefore, despite the lack of sequence conservation, Schizosaccharomyces centromere DNA possesses intrinsic conserved properties that promote assembly of CENP-A chromatin.
    Subject(s): Assembling ; Biodiversity ; Centromere - genetics ; Centromere - metabolism ; Centromere Protein A - genetics ; Centromere Protein A - metabolism ; Centromeres ; Chromatin - metabolism ; Chromatin Assembly and Disassembly - genetics ; Chromatin remodeling ; Chromosomal Proteins, Non-Histone - genetics ; Chromosomal Proteins, Non-Histone - metabolism ; Conservation ; Conserved Sequence ; Deoxyribonucleic acid ; DNA ; DNA - metabolism ; Epigenesis, Genetic ; Epigenetics ; Evolutionary genetics ; Genes ; Genomes ; Histone variants ; Histones ; Kinetochores ; Life Sciences ; Multidisciplinary Sciences ; Nucleotide sequence ; Populations and Evolution ; RNA, Ribosomal, 5S ; RNA, Transfer ; rRNA 5S ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Science & Technology ; Science & Technology - Other Topics ; Sequences ; Synteny ; tRNA ; Yeast ; Yeasts
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 8
    Language: English
    In: Genetics (Austin), 2017-10, Vol.207 (2), p.357-367
    Description: Eukaryotic genomes are rich in transcription units encoding "long noncoding RNAs" (lncRNAs). The purpose of all this transcription is unclear since most lncRNAs are quickly targeted for destruction during synthesis or shortly thereafter. As debates continue over the functional significance of many specific lncRNAs, support grows for the notion that the act of transcription rather than the RNA product itself is functionally important in many cases. Indeed, this alternative mechanism might better explain how low-abundance lncRNAs transcribed from noncoding DNA function in organisms. Here, we highlight some of the recently emerging features that distinguish coding from noncoding transcription and discuss how these differences might have important implications for the functional consequences of noncoding transcription.
    Subject(s): Abundance ; Animals ; Cancer ; Chromatin ; Chromatin - genetics ; Chromatin - metabolism ; Deoxyribonucleic acid ; DNA ; Gene expression ; gene regulation ; Genomes ; Genomics ; Humans ; long noncoding RNA (lncRNA) ; nascent transcription ; noncoding transcription ; Proteins ; Ribonucleic acid ; RNA ; RNA Polymerase II - metabolism ; RNA Polymerase II transcription ; RNA Stability ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; Stem cells ; Transcription ; transcription cycle ; Transcription, Genetic ; transcriptional interference
    ISSN: 0016-6731
    E-ISSN: 1943-2631
    Source: Alma/SFX Local Collection
    Source: Genetics Society of America
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  • 9
    Language: English
    In: Nature communications, 2020-07-27, Vol.11 (1), p.3739-3739
    Description: The PIWI protein MIWI2 and its associated PIWI-interacting RNAs (piRNAs) instruct DNA methylation of young active transposable elements (TEs) in the male germline. piRNAs are proposed to recruit MIWI2 to the transcriptionally active TE loci by base pairing to nascent transcripts, however the downstream mechanisms and effector proteins utilized by MIWI2 in directing de novo TE methylation remain incompletely understood. Here, we show that MIWI2 associates with TEX15 in foetal gonocytes. TEX15 is predominantly a nuclear protein that is not required for piRNA biogenesis but is essential for piRNA-directed TE de novo methylation and silencing. In summary, TEX15 is an essential executor of mammalian piRNA-directed DNA methylation.
    Subject(s): Animals ; Argonaute Proteins - genetics ; Argonaute Proteins - metabolism ; Cell Cycle Proteins - metabolism ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - genetics ; DNA Transposable Elements - genetics ; Female ; Fetus - cytology ; Gene Silencing ; Genome ; Germ cells ; Germ Cells - metabolism ; Male ; Mammals ; Mice ; Mice, Inbred C57BL ; Piwi RNAs ; Protein Binding ; Proteins ; Spermatogenesis ; Testis - metabolism ; Transposons
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 10
    Language: English
    In: Nucleic acids research, 2016-12-15, Vol.44 (22), p.10619-10630
    Description: Long non-coding RNA (lncRNA) transcription into a downstream promoter frequently results in transcriptional interference. However, the mechanism of this repression is not fully understood. We recently showed that drug tolerance in fission yeast Schizosaccharomyces pombe is controlled by lncRNA transcription upstream of the tgp1 permease gene. Here we demonstrate that transcriptional interference of tgp1 involves several transcription-coupled chromatin changes mediated by conserved elongation factors Set2, Clr6CII, Spt6 and FACT. These factors are known to travel with RNAPII and establish repressive chromatin in order to limit aberrant transcription initiation from cryptic promoters present in gene bodies. We therefore conclude that conserved RNAPII-associated mechanisms exist to both suppress intragenic cryptic promoters during genic transcription and to repress gene promoters by transcriptional interference. Our analyses also demonstrate that key mechanistic features of transcriptional interference are shared between S. pombe and the highly divergent budding yeast Saccharomyces cerevisiae Thus, transcriptional interference is an ancient, conserved mechanism for tightly controlling gene expression. Our mechanistic insights allowed us to predict and validate a second example of transcriptional interference involving the S. pombe pho1 gene. Given that eukaryotic genomes are pervasively transcribed, transcriptional interference likely represents a more general feature of gene regulation than is currently appreciated.
    Subject(s): Acid Phosphatase - genetics ; Acid Phosphatase - metabolism ; Chromatin - genetics ; Chromatin - metabolism ; Gene Expression Regulation, Fungal ; Gene regulation, Chromatin and Epigenetics ; Gene Silencing ; Genes, Fungal ; Histone-Lysine N-Methyltransferase - genetics ; Histone-Lysine N-Methyltransferase - metabolism ; Histones ; Methylation ; Promoter Regions, Genetic ; Protein Processing, Post-Translational ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Transcription, Genetic
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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