Characterization of the grappa Gene, the Drosophila Histone H3 Lysine 79 Methyltransferase

Shanower, Gregory; Müller, Martin; Blanton, Jason; Honti, Viktor; Gyurkovics, Henrik; Schedl, Paul

doi:10.1534/genetics.104.033191

Cited by 123 publications

(135 citation statements)

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“…Recent evidence further supports this idea: the only established TPE modifier, gpp, codes for a protein with an H3Me2K79 histonemethyltransferase activity, and shows genetic interactions with the Pc-G genes (Shanower et al, 2005). However, no data are available to prove a direct effect, as H3Me2K79 is not present at the telomeres (Shanower et al, 2005), whereas the tri-methyl isoform is absent from Drosophila (McKittrick et al, 2004). The effects of many other described TPE modifiers require thorough reassessment (Mason et al, 2004), as the early screenings for TPE modifiers did not account for the possible influence of the genetic background (Cryderman et al, 1999;Boivin et al, 2003).…”

Section: Discussionmentioning

confidence: 92%

“…Taking into account the parallels between PRE and TAS, and the fact that both PRE and TAS bind repressive Pc-G complexes of proteins, TAS appear to represent the regions of Pc-G-mediated silencing (Boivin et al, 2003). Recent evidence further supports this idea: the only established TPE modifier, gpp, codes for a protein with an H3Me2K79 histonemethyltransferase activity, and shows genetic interactions with the Pc-G genes (Shanower et al, 2005). However, no data are available to prove a direct effect, as H3Me2K79 is not present at the telomeres (Shanower et al, 2005), whereas the tri-methyl isoform is absent from Drosophila (McKittrick et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Three distinct chromatin domains in telomere ends of polytene chromosomes inDrosophila melanogaster Telmutants

Andreyeva

Belyaeva

Semeshin

et al. 2005

Journal of Cell Science

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IntroductionTelomeres are specialized DNA-protein complexes that cap the termini of linear chromosomes. They compensate for incomplete DNA replication and contribute to the stability of chromosomes and karyotype (Muller, 1932;Pardue and Debaryshe, 1999;Biessmann and Mason, 2003). Telomeres also participate in nuclear architecture maintenance, and are known to associate with nuclear lamina (Hochstrasser et al., 1986;Marshall et al., 1996;Hari et al., 2001) or with nuclear matrix (de Lange, 1992;Luderus et al., 1996). However, the factors that underlie these phenomena, as well as the mechanisms of telomere functioning, remain poorly understood in Drosophila melanogaster.In eukaryotes, such as budding yeast, fission yeast and humans, telomeres are considered to be essentially heterochromatic (Perrod and Gasser, 2003). Heterochromatin is characterized by a high degree of DNA compaction, late replication in S phase, and by association with specific silencing proteins (Richards and Elgin, 2002). Intercalary (IH) and pericentric heterochromatin regions in many Diptera species are characterized by DNA underreplication and nonhomologous (ectopic) pairing of chromosomal regions in polytene chromosomes (Zhimulev, 1998). The question whether D. melanogaster telomeres are heterochromatic in

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Three distinct chromatin domains in telomere ends of polytene chromosomes inDrosophila melanogaster Telmutants

Andreyeva

Belyaeva

Semeshin

et al. 2005

Journal of Cell Science

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“…Mutations in gpp, a gene that encodes the histone H3 lysine 79 methytransferase, also act as dominant suppressors of TPE (Shanower et al 2005). We, therefore, asked what effect the gpp XXV mutation has on expression of the EPgy2 insertions in the terminal array.…”

Section: Resultsmentioning

confidence: 99%

Two Distinct Domains in Drosophila melanogaster Telomeres

et al. 2005

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Telomeres are generally considered heterochromatic. On the basis of DNA composition, the telomeric region of Drosophila melanogaster contains two distinct subdomains: a subtelomeric region of repetitive DNA, termed TAS, and a terminal array of retrotransposons, which perform the elongation function instead of telomerase. We have identified several P-element insertions into this retrotransposon array and compared expression levels of transgenes with similar integrations into TAS and euchromatic regions. In contrast to insertions in TAS, which are silenced, reporter genes in the terminal HeT-A, TAHRE, or TART retroelements did not exhibit repressed expression in comparison with the same transgene construct in euchromatin. These data, in combination with cytological studies, provide evidence that the subtelomeric TAS region exhibits features resembling heterochromatin, while the terminal retrotransposon array exhibits euchromatic characteristics. D NA sequences at the ends of eukaryotic chromosomes are the products of a telomere elongation process. In most eukaryotes, these sequences are simple repeating units that are synthesized by telomerase, but in Drosophila melanogaster they are tandem head-to-tail arrays of three non-long terminal repeat retrotransposons, HeT-A, TAHRE, and TART ( Despite these differences, a common feature of eukaryotic chromosomes is a region of complex repeats located adjacent to the terminal sequences. These complex repeats are referred to as subtelomeric regions, or telomere-associated sequences (TAS), and differ in sequence, structure, and length among species and among telomeres within an individual (Pryde et al. 1997). The repetitive nature and the high density of transposable elements in these subtelomeric regions (Mefford and Trask 2002) are reminiscent of heterochromatin. In D. melanogaster, TAS consist of several kilobases of complex repeats, which exhibit similarities between the different chromosome ends. Sequences of the 2L and X TAS regions have been described in detail (Karpen and Spradling 1992;Walter et al. 1995), and in situ hybridizations to polytene chromosomes showed that 2L TAS share homology with 3L TAS, while X TAS share homology with 2R and 3R TAS. The 2L TAS appear to be 15 kb in length and composed of relatively simple

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“…The mammalian homolog, DOT1L, has been shown to be required for embryogenesis, hematopoiesis, and cardiac function (17)(18)(19)(20). DOT1L was recently identified as an essential and dedicated enzyme for Wnt target-gene activation in the intestine and needed for the expression of genes that require high levels of Wnt signaling in Drosophila (12, 13).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

Betancourt

Cailotto

Kerkhof

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

124

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Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW ( P = 4.8 × 10 −10 ). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10 −11 . The SNP was also strongly associated with a 12% reduced risk for HOA ( P = 1 × 10 −4 ). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.

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Characterization of the grappa Gene, the Drosophila Histone H3 Lysine 79 Methyltransferase

Cited by 123 publications

References 32 publications

Three distinct chromatin domains in telomere ends of polytene chromosomes inDrosophila melanogaster Telmutants

Three distinct chromatin domains in telomere ends of polytene chromosomes inDrosophila melanogaster Telmutants

Two Distinct Domains in Drosophila melanogaster Telomeres

Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

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