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Keywords = CTDNEP1

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14 pages, 3079 KiB  
Article
Multiomics Screening Identified CpG Sites and Genes That Mediate the Impact of Exposure to Environmental Chemicals on Cardiometabolic Traits
by Majid Nikpay
Epigenomes 2024, 8(3), 29; https://doi.org/10.3390/epigenomes8030029 - 29 Jul 2024
Viewed by 1482
Abstract
An understanding of the molecular mechanism whereby an environmental chemical causes a disease is important for the purposes of future applications. In this study, a multiomics workflow was designed to combine several publicly available datasets in order to identify CpG sites and genes [...] Read more.
An understanding of the molecular mechanism whereby an environmental chemical causes a disease is important for the purposes of future applications. In this study, a multiomics workflow was designed to combine several publicly available datasets in order to identify CpG sites and genes that mediate the impact of exposure to environmental chemicals on cardiometabolic traits. Organophosphate and prenatal lead exposure were previously reported to change methylation level at the cg23627948 site. The outcome of the analyses conducted in this study revealed that, as the cg23627948 site becomes methylated, the expression of the GNA12 gene decreases, which leads to a higher body fat percentage. Prenatal perfluorooctane sulfonate exposure was reported to increase the methylation level at the cg21153102 site. Findings of this study revealed that higher methylation at this site contributes to higher diastolic blood pressure by changing the expression of CHP1 and GCHFR genes. Moreover, HKR1 mediates the impact of B12 supplementation → cg05280698 hypermethylation on higher kidney function, while CTDNEP1 mediates the impact of air pollution → cg03186999 hypomethylation on higher systolic blood pressure. This study investigates CpG sites and genes that mediate the impact of environmental chemicals on cardiometabolic traits. Furthermore, the multiomics approach described in this study provides a convenient workflow with which to investigate the impact of an environmental factor on the body’s biomarkers, and, consequently, on health conditions, using publicly available data. Full article
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Figure 1
<p>Overview of the multiomics approach used in this study to investigate the molecular path through which an environmental chemical impacts a cardiometabolic trait. Initially, the list of CpG sites that underwent chemical modification as a result of exposure to environmental chemicals were obtained from the EWAS Atlas. Then, colocalization analysis was performed to identify genomic regions that the SNPs underlying a CpG site and a cardiometabolic trait correlate with. Significant CpG–trait pairs from this stage were then subjected to Mendelian randomization to determine if changes in the methylation level at a CpG site have a causal impact on a cardiometabolic trait (<span class="html-italic">p</span> &lt; 5 × 10<sup>−8</sup>). Finally, to obtain functional insight, eQTL data from the eQTLGen consortium were integrated to investigate genes that convey the impact of a CpG site on a trait.</p>
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<p>The mechanism whereby cg23627948 mediates the impact of environmental chemicals on obesity: (<b>A</b>) regional association plots for mQTLs of cg23627948, eQTLs of <span class="html-italic">GNA12</span>, and risk SNPs of obesity overlap; and (<b>B</b>) the cg23627948 site is reported to undergo chemical modification as a result of exposure to environmental factors such as organophosphates and lead (<a href="#epigenomes-08-00029-t003" class="html-table">Table 3</a>). Findings from the MR analysis indicated that higher methylation at cg23627948 leads to lower expression of <span class="html-italic">GNA12</span>; this consequently contributes to higher body fat percentage. Complete statistical details are available in <a href="#epigenomes-08-00029-t004" class="html-table">Table 4</a>. Points on MR plots represent SNPs; the x-value of an SNP is its effect size on the predictor, the horizontal error bar indicates the standard error around the effect size. Similarly, the y-value of the SNP indicates its effect size on the outcome, and the vertical error bar indicates the standard error. The dashed line represents the line of best fit (a line with the intercept of 0 and the slope of B from the MR test).</p>
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<p>Higher methylation at cg21153102 site contributes to diastolic blood pressure (DBP) by changing the expression of <span class="html-italic">GCHFR</span> and <span class="html-italic">CHP1</span>. cg21153102 undergoes chemical modification as a result of exposure to perfluorooctane sulfonate (<a href="#epigenomes-08-00029-t003" class="html-table">Table 3</a>). I noted that as the cg21153102 site becomes methylated it increases the expression of <span class="html-italic">GCHFR</span> but lowers levels of <span class="html-italic">CHP1</span>. This consequently leads to higher DBP, because a higher expression of <span class="html-italic">GCHFR</span> and a lower level of <span class="html-italic">CHP1</span> are associated with higher DBP levels. Complete statistical details are available in <a href="#epigenomes-08-00029-t004" class="html-table">Table 4</a>. Points on MR plots represent SNPs; the x-value of an SNP is its effect size on the predictor, and the horizontal error bar indicates the standard error around the effect size. Similarly, the y-value of the SNP indicates its effect size on the outcome, and the vertical error bar indicates the standard error. The dashed line represents the line of best fit (a line with the intercept of 0 and the slope of B from the MR test).</p>
Full article ">Figure 4
<p>The mechanism whereby cg05280698 exerts the impact of vitamin B12 supplementation on kidney function: (<b>A</b>) regional association plots for mQTLs of cg05280698, eQTLs of <span class="html-italic">HKR1</span> and SNPs for kidney function overlap. The cg05280698 site is reported to become hypermethylated in people who take vitamin B12 supplementation (<a href="#epigenomes-08-00029-t003" class="html-table">Table 3</a>); and (<b>B</b>) MR analysis revealed that as the site becomes methylated, the expression of <span class="html-italic">HKR1</span> decreases and that this leads to higher kidney function. Complete statistical details are available in <a href="#epigenomes-08-00029-t004" class="html-table">Table 4</a>. Points on MR plots represent SNPs; the x-value of an SNP is its effect size on the predictor, and the horizontal error bar indicates the standard error around the effect size. Similarly, the y-value of the SNP indicates its effect size on the outcome, and the vertical error bar indicates the standard error. The dashed line represents the line of best fit (a line with the intercept of 0 and the slope of B from the MR test).</p>
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<p>cg03186999 mediates the impact of air pollution on systolic blood pressure (SBP) by lowering the expression of <span class="html-italic">CTDNEP1</span>: (<b>A</b>) I noted an overlap between mQTLs of cg03186999, SNPs for SBP, and eQTLs for <span class="html-italic">CTDNEP1</span>. The cg03186999 site is reported to be hypomethylated in individuals exposed to air pollution (<a href="#epigenomes-08-00029-t003" class="html-table">Table 3</a>); and (<b>B</b>) the outcome of the MR analysis confirmed that as the cg03186999 site becomes hypomethylated, the expression of <span class="html-italic">CTDNEP1</span> decreases; this leads to higher SBP. Complete statistical details are available in <a href="#epigenomes-08-00029-t004" class="html-table">Table 4</a>. Points on MR plots represent SNPs; the x-value of an SNP is its effect size on the predictor, and the horizontal error bar indicates the standard error around the effect size. Similarly, the y-value of the SNP indicates its effect size on the outcome, and the vertical error bar indicates the standard error. The dashed line represents the line of best fit (a line with the intercept of 0 and the slope of B from the MR test).</p>
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13 pages, 2407 KiB  
Review
Research Trends in C-Terminal Domain Nuclear Envelope Phosphatase 1
by Harikrishna Reddy Rallabandi, Haewon Choi, Hyunseung Cha and Young Jun Kim
Life 2023, 13(6), 1338; https://doi.org/10.3390/life13061338 - 7 Jun 2023
Cited by 4 | Viewed by 1815
Abstract
C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly Dullard) is a member of the newly emerging protein phosphatases and has been recognized in neuronal cell tissues in amphibians. It contains the phosphatase domain in the C-terminal, and the sequences are conserved in various [...] Read more.
C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly Dullard) is a member of the newly emerging protein phosphatases and has been recognized in neuronal cell tissues in amphibians. It contains the phosphatase domain in the C-terminal, and the sequences are conserved in various taxa of organisms. CTDNEP1 has several roles in novel biological activities such as neural tube development in embryos, nuclear membrane biogenesis, regulation of bone morphogenetic protein signaling, and suppression of aggressive medulloblastoma. The three-dimensional structure of CTDNEP1 and the detailed action mechanisms of CTDNEP1’s functions have yet to be determined for several reasons. Therefore, CTDNEP1 is a protein phosphatase of interest due to recent exciting and essential works. In this short review, we summarize the presented biological roles, possible substrates, interacting proteins, and research prospects of CTDNEP1. Full article
(This article belongs to the Collection Feature Review Papers for Life)
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Figure 1

Figure 1
<p>The multiple sequence alignments of CTDNEP1 homologs produced using T-Coffee (<a href="https://tcoffee.crg.eu/" target="_blank">https://tcoffee.crg.eu/</a>, accessed on 19 March 2023). GenBank accession numbers corresponding to the homologs are given below; Homo sapiens, NP_0001137247.1; Pan troglodytes, XP_511976.3; Bos taurus, NP_001039491.1; Mus musculus, NP_080293.1; Xenopus tropicalis, NP_001017177.1; Danio rerio, NP_001007310.1, NP_001007441.1; Drosophila melanogaster, NP_608449.1; Caenorhabditis elegans, NP_001254123.1. DLDET represents the active site sequences, and the transmembrane region is presented as a blue bar. The dark pink colors are reliable alignments, while the green colors are unreliable alignments. The yellow colors are moderately reliable alignments. The cons means the degree of conservation observed in each column, which is denoted by the following symbols; an * (asterisk) indicates positions which have a single, fully conserved residue; a : (colon) indicates conservation between groups of strongly similar properties; a . (period) indicates conservation between groups of weakly similar properties.</p>
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<p>The structural comparison of human CTDNEP1 (<b>d</b>), a model structure predicted using alphafold2) with human CTDSP1 (<b>a</b>), pdb ID = 2ghq, a complex structure of the green-colored CTD phosphatase domain of CTDSP1 with the other colored CTD peptide of RNAPII), human CTDSP2 (<b>b</b>), pdb ID = 2q5e, an apo structure of the green-colored CTD phosphatase domain of CTDSP2), and human CTDSPL (<b>c</b>), pdb ID = 2hhl, a complex structure of the green-colored CTD phosphatase domain of CTDSPL with the other colored phosphatase inhibitor). In the model structure of CTDNEP1, the blue color represents very high per-residue confidence (pLDDT &gt; 90), and the sky-blue color represents high confidence (90 &gt; pLDDT &gt; 70). The yellow color represents low confidence (70 &gt; pLDDT &gt; 50).</p>
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