Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA300410 | ENA |
REPOSITORIES: ENA
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Project description:Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1+/- specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1+/- specific signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing. Bisulphite converted DNA from 122 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip array.
2015-12-16 | E-GEOD-74432 | biostudies-arrayexpress
Project description:Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1+/- specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1+/- specific signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
2015-12-16 | GSE74432 | GEO
Project description:Overgrowth with Intellectual Disability (OGID) is characterized by generalized overgrowth, including a head circumference and/or height ≥ 2 standard deviations (s.d.) above the mean, accompanied by mild to moderate intellectual disability. Sotos Syndrome, the most common form of OGID, results from loss-of-function (LoF) mutations in NSD1, which encodes a histone methyltransferase. Another major OGID subtype, Tatton-Brown-Rahman syndrome, is caused by LoF mutations in DNMT3A, encoding a de novo DNA methyltransferase. In contrast, gain-of-function (GoF) mutations in DNMT3A cause Heyn-Sproul-Jackson syndrome, characterized by growth restriction and microcephaly. We hypothesize that NSD1 LoF and DNMT3A LoF mutations share a convergent DNA methylation signature that is distinct from the pattern seen in DNMT3A GoF mutations. To test this, we generated human embryonic stem cell lines carrying these growth syndrome-associated mutations in NSD1 and DNMT3A, profiled their DNA methylation patterns using the Illumina EPIC array, and analyzed both shared and unique methylation phenotypes.
2025-07-14 | GSE301386 | GEO
Project description:Overgrowth with Intellectual Disability (OGID) is characterized by generalized overgrowth, including a head circumference and/or height ≥ 2 standard deviations (s.d.) above the mean, accompanied by mild to moderate intellectual disability. Sotos Syndrome, the most common form of OGID, results from loss-of-function (LoF) mutations in NSD1, which encodes a histone methyltransferase. Another major OGID subtype, Tatton-Brown-Rahman syndrome, is caused by LoF mutations in DNMT3A, encoding a de novo DNA methyltransferase. In contrast, gain-of-function (GoF) mutations in DNMT3A cause Heyn-Sproul-Jackson syndrome, characterized by growth restriction and microcephaly. We hypothesize that NSD1 LoF and DNMT3A LoF mutations share a convergent DNA methylation signature that is distinct from the pattern seen in DNMT3A GoF mutations. To test this, we generated human embryonic stem cell lines carrying these growth syndrome-associated mutations in NSD1 and DNMT3A, profiled their DNA methylation patterns using the Illumina EPIC array, and analyzed both shared and unique methylation phenotypes.
2025-07-14 | GSE299394 | GEO
Project description:Genome-wide DNA methylation signature in lung adenocarcinomas has prognostic impact
| PRJNA278141 | ENA
Project description:Gene methylation profiling of immortalized human mesenchymal stem cells comparing HPV E6/E7-transfected MSCs cells with human telomerase reverse transcriptase (hTERT)- and HPV E6/E7-transfected MSCs. hTERT may increase gene methylation in MSCs. Goal was to determine the effects of different transfected genes on global gene methylation in MSCs.
2011-08-25 | GSE23936 | GEO
Project description:Enzymes catalyzing CpG methylation in DNA, including DNMT1 and DNMT3A/B, are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting a critical role of DNA methylation during cell fate specification and maintenance. Recent studies suggest that histone post-translational modifications (PTMs) are involved in specifying patterns of DNMT localization and DNA methylation at promoters and actively transcribed gene bodies. However, mechanisms governing the establishment and maintenance of intergenic DNA methylation remain poorly understood. Germline mutations in DNMT3A lead to a childhood overgrowth syndrome that is phenotypically overlapping with Sotos syndrome caused by haploinsufficiency of NSD1, a histone methyltransferase catalyzing di-methylation on H3K36 (H3K36me2), pointing to a potential mechanistic link between the two disorders. Here we report that NSD1-mediated H3K36me2 is required for recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows binding and activity of DNMT3A are co-localized with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of NSD1 and its paralogue NSD2 in mouse and human cells redistributes DNMT3A to H3K36me3-marked gene bodies and reduces intergenic DNA methylation. NSD1 mutant tumors and Sotos patient samples are also associated with intergenic DNA hypomethylation. Consistently, PWWP-domain of DNMT3A shows dual recognition of H3K36me2/3 in vitro with a higher binding affinity towards H3K36me2, which is abrogated by overgrowth syndrome-derived missense mutations. Taken together, our study uncovers a trans-chromatin regulatory pathway that, when perturbed, promotes neoplastic and developmental overgrowth.
2019-08-30 | GSE118785 | GEO
Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Experiment Overall Design: Total RNA was extracted from stably transformed progenitors cultured in vitro and the expression levels of mRNA transcripts quantified using the Affymetrix GeneChip Mouse Genome 430 2.0 array, as previously described. The GEO database accession numbers: for progenitors immortalized by HoxA9 (GSM190542, GSM190546, GSM190547); for progenitors immortalized by coexpressed HoxA9 plus Meis1 (GSM190548, GSM190549, GSM190550); for progenitors immortalized by NUP98-NSD1 (GSM190551, GSM190552, GSM190553); and for progenitors immortalized by MLL-ENL (GSM190554). Experiment Overall Design: NOTE: CEL files and dChip data were requested by GEO but not provided.
2008-06-11 | E-GEOD-10071 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation signature in lung adenocarcinomas has prognostic impact [gene expression]
| PRJNA278125 | ENA