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- Engström, Karin, et al.
(author)
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Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women
- 2017
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In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:5, s. 2067-2078
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Journal article (peer-reviewed)abstract
- Arsenic, a carcinogen with immunotoxic effects, is a common contaminant of drinking water and certain food worldwide. We hypothesized that chronic arsenic exposure alters gene expression, potentially by altering DNA methylation of genes encoding central components of the immune system. We therefore analyzed the transcriptomes (by RNA sequencing) and methylomes (by target-enrichment next-generation sequencing) of primary CD4-positive T cells from matched groups of four women each in the Argentinean Andes, with fivefold differences in urinary arsenic concentrations (median concentrations of urinary arsenic in the lower- and high-arsenic groups: 65 and 276 mu g/l, respectively). Arsenic exposure was associated with genome-wide alterations of gene expression; principal component analysis indicated that the exposure explained 53% of the variance in gene expression among the top variable genes and 19% of 28,351 genes were differentially expressed (false discovery rate < 0.05) between the exposure groups. Key genes regulating the immune system, such as tumor necrosis factor alpha and interferon gamma, as well as genes related to the NF-kappa-beta complex, were significantly downregulated in the high-arsenic group. Arsenic exposure was associated with genome-wide DNA methylation; the high-arsenic group had 3% points higher genome-wide full methylation (> 80% methylation) than the lower-arsenic group. Differentially methylated regions that were hyper-methylated in the high-arsenic group showed enrichment for immune-related gene ontologies that constitute the basic functions of CD4-positive T cells, such as isotype switching and lymphocyte activation and differentiation. In conclusion, chronic arsenic exposure from drinking water was related to changes in the transcriptome and methylome of CD4-positive T cells, both genome wide and in specific genes, supporting the hypothesis that arsenic causes immunotoxicity by interfering with gene expression and regulation.
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| 3. |
- Marabita, Francesco, et al.
(author)
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Expression of Transient Receptor Potential Channels in the Purified Human Pancreatic beta-Cells
- 2017
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In: Pancreas. - : LIPPINCOTT WILLIAMS & WILKINS. - 0885-3177 .- 1536-4828. ; 46:1, s. 97-101
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Journal article (peer-reviewed)abstract
- Objective: Members of the transient receptor potential (TRP) channels are involved in mediating the electrical excitability and stimulus-secretion coupling in the pancreatic beta-cells. The expression and the relative abundance of different TRP channels in the human beta-cells are unknown. The objective of this study was to examine the expression of the TRP channels and their relative abundance in the human beta-cell. Methods: RNA sequencing data obtained from human islets, fluorescence-activated cell sorting-purified human beta-cell and human pancreatic acinar cells were analyzed. Gene counts and fragments per kilobase per million mapped reads were obtained. Results: Among the TRPC family only the TRPC1 was expressed in the human beta-cell. TRPV1 channels were not expressed in the human beta-cells. Among the TRPM family, TRPM4, TRPM7, TRPM2, and TRPM3 were expressed in the human beta-cell. Of the remaining TRP channels, TRPP2, TRPML1, and TRPML3 were expressed in these cells. Conclusions: By analyzing the RNA sequencing data, we have detected for the first time the TRP channels that are expressed in the purified human beta-cells, in comparison to the other relevant pancreatic cell types. Our study provides an opportunity to focus on these TRP channels for a better understanding of the electrophysiology and stimulus-secretion coupling in these cells.
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| 4. |
- Marabita, Francesco, et al.
(author)
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Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
- 2022
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In: Cell Systems. - : Cell Press. - 2405-4712 .- 2405-4720. ; 13:3, s. 241-255.e7
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Journal article (peer-reviewed)abstract
- We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper's transparent peer review process is included in the supplemental information.
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| 5. |
- Tobiasson, Magnus, et al.
(author)
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Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease
- 2017
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:17, s. 28812-28825
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Journal article (peer-reviewed)abstract
- Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.
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