Genetics of Sotos syndrome

Visser, Remco; Matsumoto, Naomichi

doi:10.1097/00008480-200312000-00010

Cited by 53 publications

(39 citation statements)

References 110 publications

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“…Deletions and translocations involving WHSC1 are associated with Wolf-Hirschhorn syndrome and multiple myeloma (34). Haploinsufficiency of nuclear receptor-binding SET domain 1 (NSD1), due to intragenic mutations or submicroscopic deletions, causes Sotos syndrome (36). Mutations in the mismatch repair gene MSH6 predispose to hereditary non-poliposis colorectal cancer (27).…”

Section: Discussionmentioning

confidence: 99%

The PWWP Domain of Dnmt3a and Dnmt3b Is Required for Directing DNA Methylation to the Major Satellite Repeats at Pericentric Heterochromatin

Chen

Tsujimoto

2004

Molecular and Cellular Biology

240

210

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Dnmt3a and Dnmt3b are responsible for the establishment of DNA methylation patterns during development. These proteins contain, in addition to a C-terminal catalytic domain, a unique N-terminal regulatory region that harbors conserved domains, including a PWWP domain. The PWWP domain, characterized by the presence of a highly conserved proline-tryptophan-tryptophan-proline motif, is a module of 100 to 150 amino acids found in many chromatin-associated proteins. However, the function of the PWWP domain remains largely unknown. In this study, we provide evidence that the PWWP domains of Dnmt3a and Dnmt3b are involved in functional specialization of these enzymes. We show that both endogenous and green fluorescent protein-tagged Dnmt3a and Dnmt3b are particularly concentrated in pericentric heterochromatin. Mutagenesis analysis indicates that their PWWP domains are required for their association with pericentric heterochromatin. Disruption of the PWWP domain abolishes the ability of Dnmt3a and Dnmt3b to methylate the major satellite repeats at pericentric heterochromatin. Furthermore, we demonstrate that the Dnmt3a PWWP domain has little DNA-binding ability, in contrast to the Dnmt3b PWWP domain, which binds DNA nonspecifically. Collectively, our results suggest that the PWWP domains of Dnmt3a and Dnmt3b are essential for targeting these enzymes to pericentric heterochromatin, probably via a mechanism other than protein-DNA interactions.

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Section: Discussionmentioning

confidence: 99%

The PWWP Domain of Dnmt3a and Dnmt3b Is Required for Directing DNA Methylation to the Major Satellite Repeats at Pericentric Heterochromatin

Chen

Tsujimoto

2004

Molecular and Cellular Biology

240

210

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“…Haploinsufficiency of the NSD1 gene leads to Sotos syndrome, which is a neurological disorder characterized by overgrowth in childhood, advanced bone age, craniofacial abnormalities, mental retardation, and possibly a susceptibility to cancer (11,12). In addition, translocation of the NSD1 gene leads to the development of certain leukemias (13).…”

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confidence: 99%

Spatial Distribution of Di- and Tri-methyl Lysine 36 of Histone H3 at Active Genes

Bannister

Schneider

Myers

et al. 2005

Journal of Biological Chemistry

387

276

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Methylation of lysine 4 of histone H3 (K4/H3) is linked to transcriptional activity, whereas methylation of K9/H3 is tightly associated with gene inactivity. These are well characterized sites of methylation within histones, but there are numerous other, less characterized, sites of modification. In Saccharomyces cerevisiae, methylation of K36/H3 has been linked to active genes, but little is known about this methylation in higher eukaryotes. Here we analyzed for the first time the levels and spatial distribution of di-and tri-methyl (di-and tri-Me) K36/H3 in metazoan genes. We analyzed chicken genes that are developmentally regulated, constitutively active, or inactive. We found that active genes contain high levels of these modifications compared with inactive genes. Furthermore, in actively transcribed regions the levels of di-and tri-Me K36/H3 peak toward the 3 end of the gene. This is in striking contrast to the distributions of di-and tri-Me K4/H3, which peak early in actively transcribed regions. Thus, di/tri-Me K4/H3 and di/tri-Me K36/H3 are both useful markers of active genes, but their genic distribution indicates differing roles. Our data suggest that the unique spatial distribution of di-and tri-Me K36/H3 plays a role in transcriptional termination and/or early RNA processing.

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“…In mice, it has been proposed that the methylation of H3-K36 and H4-K20 by the Nuclear receptorbinding SET Domain-containing protein (NSD1) is essential for early postimplantation development (36). Mutations in this gene cause the Soto's syndrome in humans, a disorder characterized by overgrowth of neural tissues, heart defects, advanced bone age, developmental delays, and increased risk of cancers (22,52). In metazoans, active genes contain higher levels of di-and trimethylated K36 compared to inactive genes (3).…”

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confidence: 99%

Methylation of Histone H3 Lysine 36 Is Required for Normal Development in Neurospora crassa

et al. 2005

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The SET domain is an evolutionarily conserved domain found predominantly in histone methyltransferases (HMTs). The Neurospora crassa genome includes nine SET domain genes (set-1 through set-9) in addition to dim-5, which encodes a histone H3 lysine 9 HMT required for DNA methylation. We demonstrate that Neurospora set-2 encodes a histone H3 lysine 36 (K36) methyltransferase and that it is essential for normal growth and development. We used repeat induced point mutation to make a set-2 mutant (set-2 RIP1 ) with multiple nonsense mutations. Western analyses revealed that the mutant lacks SET-2 protein and K36 methylation. An amino-terminal fragment that includes the AWS, SET, and post-SET domains of SET-2 proved sufficient for K36 HMT activity in vitro. Nucleosomes were better substrates than free histones. The set-2 RIP1 mutant grows slowly, conidiates poorly, and is female sterile. Introducing the wild-type gene into the mutant complemented the defects, confirming that they resulted from loss of set-2 function. We replaced the wild-type histone H3 gene (hH3) with an allele producing a Lys to Leu substitution at position 36 and found that this hH3 K36L mutant phenocopied the set-2 RIP1 mutant, confirming that the observed defects in growth and development result from inability to methylate K36 of H3. Finally, we used chromatin immunoprecipitation to demonstrate that actively transcribed genes in Neurospora crassa are enriched for H3 methylated at lysines 4 and 36. Taken together, our results suggest that methylation of K36 in Neurospora crassa is essential for normal growth and development.In eukaryotes DNA is wrapped around histones, which are subject to a variety of covalent modifications (e.g., methylation, acetylation, phosphorylation, and ubiquitylation) (51, 54). These modifications are believed to alter chromatin structure by influencing histone-DNA, histone-histone, and histone-nonhistone protein interactions (16, 55). Permutations of histone modifications constitute a "histone code" that can impact chromatin-templated processes, including DNA methylation, heterochromatin formation, transcription, and DNA replication and repair (18,46). The SET [Su(var)3-9, Enhancer-of-zeste, Trithorax] domain histone methyltransferases (HMTs) constitute one group of evolutionarily conserved chromatin-modifying proteins (10,12,19,23,24,40,45,60). A well-characterized example is the Neurospora crassa DIM-5 protein, which trimethylates lysine 9 of histone H3 and directs DNA methylation (48,49,58,59). In addition to DIM-5, the N. crassa genome encodes nine other putative SET domain proteins (Fig.

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Genetics of Sotos syndrome

Cited by 53 publications

References 110 publications

The PWWP Domain of Dnmt3a and Dnmt3b Is Required for Directing DNA Methylation to the Major Satellite Repeats at Pericentric Heterochromatin

The PWWP Domain of Dnmt3a and Dnmt3b Is Required for Directing DNA Methylation to the Major Satellite Repeats at Pericentric Heterochromatin

Spatial Distribution of Di- and Tri-methyl Lysine 36 of Histone H3 at Active Genes

Methylation of Histone H3 Lysine 36 Is Required for Normal Development in Neurospora crassa

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