In vivo investigations of the effect of short- and long-term recombinant growth hormone treatment on DNA-methylation in humans
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Susanne Bens
PROVIDER: E-GEOD-57205 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Treatment with recombinant human growth hormone (rhGH) has been consistently reported to induce transcriptional changes in various human tissues including peripheral blood. For other hormones it has been shown that the induction of such transcriptional effects is conferred or at least accompanied by DNA-methylation changes. To analyse effects of short term rhGH treatment on the DNA-methylome we investigated a total of 24 patients at baseline and after 4-day rhGH stimulation. We performed array-based DNA-methylation profiling of paired peripheral blood mononuclear cell samples followed by targeted validation using bisulfite pyrosequencing. Unsupervised analysis of DNA-methylation in this short-term treated cohort revealed clustering according to individuals rather than treatment. Supervised analysis identified 239 CpGs as significantly differentially methylated between baseline and rhGH-stimulated samples (p<0.0001, unadjusted paired t-test), which nevertheless did not retain significance after adjustment for multiple testing. An individualised evaluation strategy led to the identification of 2350 CpG and 3 CpH sites showing methylation differences of at least 10% in more than 2 of the 24 analysed sample pairs. To investigate the long term effects of rhGH treatment on the DNA-methylome, we analysed peripheral blood cells from an independent cohort of 36 rhGH treated children born small for gestational age (SGA) as compared to 18 untreated controls. Median treatment interval was 33 months. In line with the groupwise comparison in the short-term treated cohort no differentially methylated targets reached the level of significance in the long-term treated cohort. We identified marked intra-individual responses of DNA-methylation to short-term rhGH treatment. These responses seem to be predominately associated with immunologic functions and show considerable inter-individual heterogeneity. The latter is likely the cause for the lack of a rhGH induced homogeneous DNA-methylation signature after short- and long-term treatment, which nevertheless is well in line with generally assumed safety of rhGH treatment. Bisulfite converted DNA of PB from 36 SGA born children treated long-term with rhGH and 18 SGA born children with no rhGH treatment (controls) were hybridized to the Illumina Infinium HumanMethylation 450k Bead Chip.
2015-01-23 | E-GEOD-57204 | biostudies-arrayexpress
Project description:Array-based DNA methylation profiling in peripheral blood leukocytes of 30 infertile men with impaired spermatogenesis as compared to 10 fertile men using the Illumina Infinium HumanMethylation 450k Bead Chip reveald 471 CpG sites (287 genes) to be differentially methylated between both groups. These CpG loci were significantly enriched for the gene ontology functions MHC class II receptor activity and piRNA binding. The latter was associated with two methylation-sensitive SNPs in the genes PIWIL1 and PIWIL2, respectivly, which showed significant allele distribution skewing in the infertile cohort. 445/471 differentially methylated CpGs were associated with SNPs, but 26 (15 genes) were not genomically templated and included the ENO1, MTA2, BRSK2 and LBX2 genes previously associated with fertility and spermatogenesis. The study identifies surrogate DNA methylation markers for idiopathic infertility in peripheral blood and suggests allele-specific DNA methylation differences at regulatory sites of genes involved in piRNA regulation to be associated with disturbed spermatogenesis. Bisulfite converted DNA of peripheral blood leukocytes from 30 infertile men and 10 fertile men as controls were hybridized to the Illumina Infinium HumanMethylation 450k Bead Chip.
2014-02-16 | E-GEOD-51245 | biostudies-arrayexpress
Project description:We sought to decrease the cell type heterogeneity of kidney tissues to increase the resolution of methylation profiles. To that end, microdissected human kidney tissue from patients are used and hybridized on Illumina HumanMethylation450 BeadChip arrays. We extract genomic DNA from microdissected human kidney tubule samples. And used these genomic DNA for the Illumina 450K beads array.
2013-09-14 | E-GEOD-50874 | biostudies-arrayexpress
Project description:Treatment with recombinant human growth hormone (rhGH) has been consistently reported to induce transcriptional changes in various human tissues including peripheral blood. For other hormones it has been shown that the induction of such transcriptional effects is conferred or at least accompanied by DNA-methylation changes. To analyse effects of short term rhGH treatment on the DNA-methylome we investigated a total of 24 patients at baseline and after 4-day rhGH stimulation. We performed array-based DNA-methylation profiling of paired peripheral blood mononuclear cell samples followed by targeted validation using bisulfite pyrosequencing. Unsupervised analysis of DNA-methylation in this short-term treated cohort revealed clustering according to individuals rather than treatment. Supervised analysis identified 239 CpGs as significantly differentially methylated between baseline and rhGH-stimulated samples (p<0.0001, unadjusted paired t-test), which nevertheless did not retain significance after adjustment for multiple testing. An individualised evaluation strategy led to the identification of 2350 CpG and 3 CpH sites showing methylation differences of at least 10% in more than 2 of the 24 analysed sample pairs. To investigate the long term effects of rhGH treatment on the DNA-methylome, we analysed peripheral blood cells from an independent cohort of 36 rhGH treated children born small for gestational age (SGA) as compared to 18 untreated controls. Median treatment interval was 33 months. In line with the groupwise comparison in the short-term treated cohort no differentially methylated targets reached the level of significance in the long-term treated cohort. We identified marked intra-individual responses of DNA-methylation to short-term rhGH treatment. These responses seem to be predominately associated with immunologic functions and show considerable inter-individual heterogeneity. The latter is likely the cause for the lack of a rhGH induced homogeneous DNA-methylation signature after short- and long-term treatment, which nevertheless is well in line with generally assumed safety of rhGH treatment. Bisulfite-converted DNA of PBMC from 24 patients before and after 4 days of rhGH treatment were hybridized to the Illumina Infinium HumanMethylation 450k BeadChip.
2015-01-23 | E-GEOD-57107 | biostudies-arrayexpress
Project description:Recent studies suggest that genetic and environmental factors do not account for all the schizophrenia risk and epigenetics also plays a role in disease susceptibility. DNA methylation is a heritable epigenetic modification that can regulate gene expression. Genome-Wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium Human Methylation450 Bead Chip. After adjusting for age and post-mortem interval (PMI), 4 641 probes corresponding to 2 929 unique genes were found to be differentially methylated. Of those genes, 1 291 were located in a CpG island and 817 were in a promoter region. These include NOS1, AKT1, DTNBP1, DNMT1, PPP3CC and SOX10 which have previously been associated with schizophrenia. More than 100 of these genes overlap with a previous DNA methylation study of peripheral blood from schizophrenia patients in which 27 000 CpG sites were analysed. Unsupervised clustering analysis of the top 3 000 most variable probes revealed two distinct groups with significantly more people with schizophrenia in cluster one compared to controls (p = 1.74x10-4). The first cluster was composed of 88% of patients with schizophrenia and only 12% controls while the second cluster was composed of 27% of patients with schizophrenia and 73% controls. These results strongly suggest that differential DNA methylation is important in schizophrenia etiology and add support for the use of DNA methylation profiles as a future prognostic indicator of schizophrenia Genome-Wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium Human Methylation450 Bead Chip.
2014-09-05 | E-GEOD-61107 | biostudies-arrayexpress
Project description:Identification of CpG sites associated to plasma TG levels Bisulphite converted DNA from 24 visceral adipose tissue (VAT) samples were hybridised to the Illumina Infinium HumanMethylation450 Beadchip. Contributor: the Multiple Tissue Human Expression Resource Consortium
2014-07-19 | E-GEOD-59524 | biostudies-arrayexpress
Project description:DNA methylation has been considered to play an important role in myogenic differentiation. In terminal differentiation of myoblasts, a chronological pattern of DNA methylation changes has been poorly understood. Using Infinium HumanMethylation450 BeadChips, we obtained and evaluated the genome-wide DNA methylation profiles of human myoblast differentiation in vitro. DNA methylation profiles of human myoblasts (day1, day3, day8, day15), human mesenchymal stem cells (1 sample) and human skeletal muscle tissues (2 samples) were obtained using Infinium HumanMethylation450 BeadChips (Illumina).
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Project description:Pilocytic astrocytomas (PA) are the most common brain tumor in pediatric patients and can cause significant morbidity, including chronic neurological deficiencies. They are characterized by activating alterations in the mitogen-activated protein kinase (MAPK) pathway, but little else is known about their development. To map the global DNA methylation profiles of these tumors, we analysed 61 PAs and 6 normal cerebellum samples using Illumina's Infinium HumanMethylation450 BeadChips. These data revealed two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and identified key neural developmental genes that are differentially methylated between the two groups. Integration with transcriptome microarray data highlighted significant expression differences, which were unexpectedly associated with a strong positive correlation between methylation and expression. Differentially methylated probes were often identified within the gene body and/or regions up- or downstream of the gene, rather than at the transcription start site. We also identified a large number of differentially methylated genes between cerebellar PAs and normal cerebellum, which included additional developmental genes. Bisulphite converted DNA from 61 PA tumours (fresh frozen) and 6 normal cerebellum (from commerical sources) were hybridised to the Illumina Infinium HumanMethylation450 BeadChips.
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Project description:A Sleeping Beauty (SB) transposon forward genetic screen was performed to identify the genes that promote osteosarcoma (OS) development and metastasis. Mutagenesis induced OS in wild type mice and accelerated it on a Trp53 deficient background. Analysis of tumors demonstrated that Trp53 deficiency is correlated with genomic instability, which was virtually absent in tumors induced by SB mutagenesis alone. Metastases developed in a subset of animals and in nearly all cases were clonal related to primary tumors. Over 200 candidate genes were identified, many of which are altered in human cancers including OS. Signaling pathways enriched for candidate genes were also identified and a subset of these pathways and genes were functionally validated and represent new targets for OS treatment. Bisulphite converted DNA from the 21 diagnosis osteosarcoma patients and 3 hOB cell line replicates were hybridised to the Illumina Infinium 450K Human Methylation Beadchip.
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Project description:We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG island–containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non– neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells. Genomic DNA was isolated from FACS-sorted human brain neuronal and nonneuronal nuclei. DNA was bisulfite converted and hybridised to the Illumina Infinium 450K Human Methylation Beadchip array. Six subjects in two technical replicate expriments were analyzed.
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