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  • 1
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    Online Resource
    An integrated epigenomic-transcriptomic landscape of lung cancer reveals novel methylation driver genes of diagnostic and therapeutic relevance
    Ivyspring International Publisher ; 2021
    In:  Theranostics Vol. 11, No. 11 ( 2021), p. 5346-5364
    Details
    In: Theranostics, Ivyspring International Publisher, Vol. 11, No. 11 ( 2021), p. 5346-5364
    Type of Medium: Online Resource
    ISSN: 1838-7640
    URL: Article
    DOI: 10.7150/thno.58385
    Language: English
    Publisher: Ivyspring International Publisher
    Publication Date: 2021
    detail.hit.zdb_id: 2592097-2
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  • 2
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    Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Journal of the American Society of Nephrology Vol. 31, No. 7 ( 2020-7), p. 1539-1554
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 7 ( 2020-7), p. 1539-1554
    Abstract: Several microRNAs have been shown to play significant roles in the development of renal injury. The microRNA miR-204-5p is highly enriched in the kidney but its involvement in chronic renal injury is unknown. In this study, the authors report that miR-204-5p abundance is significantly decreased in kidney biopsy samples from patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy. They also found, in a rat model of salt-sensitive hypertension, a mouse model of hypertension, and a mouse model of type 2 diabetes, inhibition of miR-204-5p, or deletion of the Mir204 gene results in upregulation of an injurious molecular pathway and substantial exacerbation of renal injury. These findings provide evidence of a prominent role for miR-204-5p in safeguarding the kidneys against common causes of chronic renal injury. Background Aberrant microRNA (miRNA) expression affects biologic processes and downstream genes that are crucial to CKD initiation or progression. The miRNA miR-204-5p is highly expressed in the kidney but whether miR-204-5p plays any role in the development of chronic renal injury is unknown. Methods We used real-time PCR to determine levels of miR-204 in human kidney biopsies and animal models. We generated Mir204 knockout mice and used locked nucleic acid–modified anti-miR to knock down miR-204-5p in mice and rats. We used a number of physiologic, histologic, and molecular techniques to analyze the potential role of miR-204-5p in three models of renal injury. Results Kidneys of patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy exhibited a significant decrease in miR-204-5p compared with controls. Dahl salt-sensitive rats displayed lower levels of renal miR-204-5p compared with partially protected congenic SS.13 BN26 rats. Administering anti–miR-204-5p to SS.13 BN26 rats exacerbated interlobular artery thickening and renal interstitial fibrosis. In a mouse model of hypertensive renal injury induced by uninephrectomy, angiotensin II, and a high-salt diet, Mir204 gene knockout significantly exacerbated albuminuria, renal interstitial fibrosis, and interlobular artery thickening, despite attenuation of hypertension. In diabetic db/db mice, administering anti–miR-204-5p exacerbated albuminuria and cortical fibrosis without influencing blood glucose levels. In all three models, inhibiting miR-204-5p or deleting Mir204 led to upregulation of protein tyrosine phosphatase SHP2, a target gene of miR-204-5p, and increased phosphorylation of signal transducer and activator of transcription 3, or STAT3, which is an injury-promoting effector of SHP2. Conclusions These findings indicate that the highly expressed miR-204-5p plays a prominent role in safeguarding the kidneys against common causes of chronic renal injury.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2019101100
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2029124-3
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  • 3
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    Histologically resolved small RNA maps in primary focal segmental glomerulosclerosis indicate progressive changes within glomerular and tubulointerstitial regions
    Elsevier BV ; 2022
    In:  Kidney International Vol. 101, No. 4 ( 2022-04), p. 766-778
    Details
    In: Kidney International, Elsevier BV, Vol. 101, No. 4 ( 2022-04), p. 766-778
    Type of Medium: Online Resource
    ISSN: 0085-2538
    URL: Article
    DOI: 10.1016/j.kint.2021.12.030
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2007940-0
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  • 4
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    MicroRNA-214-3p in the Kidney Contributes to the Development of Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of the American Society of Nephrology Vol. 29, No. 10 ( 2018-10), p. 2518-2528
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 10 ( 2018-10), p. 2518-2528
    Abstract: In spite of extensive study, the mechanisms for salt sensitivity of BP in humans and rodent models remain poorly understood. Several microRNAs (miRNAs) have been associated with hypertension, but few have been shown to contribute to its development. Methods We examined miRNA expression profiles in human kidney biopsy samples and rat models using small RNA deep sequencing. To inhibit an miRNA specifically in the kidney in conscious, freely moving rats, we placed indwelling catheters to allow both renal interstitial administration of a specific anti-miR and measurement of BP. A rat with heterozygous disruption of the gene encoding endothelial nitric oxide synthase (eNOS) was developed. We used bioinformatic analysis to evaluate the relationship between 283 BP-associated human single-nucleotide polymorphisms (SNPs) and 1870 human miRNA precursors, as well as other molecular and cellular methods. Results Compared with salt-insensitive SS.13 BN26 rats, Dahl salt-sensitive (SS) rats showed an upregulation of miR-214-3p, encoded by a gene in the SS.13 BN26 congenic region. Kidney-specific inhibition of miR-214-3p significantly attenuated salt-induced hypertension and albuminuria in SS rats. miR-214-3p directly targeted eNOS. The effect of miR-214-3p inhibition on hypertension and albuminuria was abrogated in SS rats with heterozygous loss of eNOS. Human kidney biopsy specimens from patients with hypertension or hypertensive nephrosclerosis showed upregulation of miR-214-3p; the gene encoding miR-214-3p was one of several differentially expressed miRNA genes located in proximity to human BP-associated SNPs. Conclusions Renal miR-214-3p plays a functional and potentially genetic role in the development of hypertension, which might be mediated in part by targeting eNOS.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2018020117
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2029124-3
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  • 5
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    A comprehensive evaluation of computational tools to identify differential methylation regions using RRBS data
    Elsevier BV ; 2020
    In:  Genomics Vol. 112, No. 6 ( 2020-11), p. 4567-4576
    Details
    In: Genomics, Elsevier BV, Vol. 112, No. 6 ( 2020-11), p. 4567-4576
    Type of Medium: Online Resource
    ISSN: 0888-7543
    URL: Article
    DOI: 10.1016/j.ygeno.2020.07.032
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1468023-3
    SSG: 12
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  • 6
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    Dietary Sodium Restriction Results in Tissue-Specific Changes in DNA Methylation in Humans
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hypertension Vol. 78, No. 2 ( 2021-08), p. 434-446
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 78, No. 2 ( 2021-08), p. 434-446
    Abstract: Dietary sodium affects blood pressure (BP) and vascular function. Animal studies suggest epigenetic changes (eg, DNA methylation) are involved. We hypothesized that sodium restriction induces methylation changes in T cells and arterioles in humans. Fifty subjects (49% women) were placed on 1200-mg sodium/day diet for 2 weeks. BP and brachial artery flow-mediated dilation were evaluated. Methylation sequencing (pre- and post-diet) was performed on T-cell (n=50) and biopsied arteriolar (n=10) DNA. RNA sequencing was also performed on arterioles (n=11). Over 2 weeks, mean sodium consumption was 946 mg/day. Average BP reductions after low-sodium intake were −8±13/−4±9 mm Hg ( P 〈 0.001). Flow-mediated dilation improved (5.8±2.9% to 6.8±3.4%; P =0.03). T-cell DNA was substantially more methylated than arterioles. The differentially methylated regions (false discovery rate, 〈 0.05) identified in T cells and arterioles after sodium restriction were located in 117 and 71 genes, respectively. Four genes were identified in both T cells and arterioles ( P =0.009 for the overlap). The dietary effects on methylation in several DNA regions were associated with dietary effects on BP. Several differentially expressed genes in arterioles contained differentially methylated regions at the significance level of P 〈 0.05. In addition, 46 genes contained differentially methylated regions in both human and SS/Mcw rat T cells ( P =0.03 for the overlap). Sodium restriction significantly affected DNA methylation in T cells and arterioles, some of which are associated with BP. Methylation patterns and sodium effects on methylation are largely tissue specific but also have overlaps between tissues and species. These findings may lead to better understanding of dietary sodium interactions with cellular processes and, therefore, novel therapeutic targets.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.120.17351
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2094210-2
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  • 7
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    Abstract P210: Mir-204 In Endothelial Cells Contributes To The Development Of Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Hypertension Vol. 79, No. Suppl_1 ( 2022-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 79, No. Suppl_1 ( 2022-09)
    Abstract: Global knockout of microRNA miR-204 leads to significant attenuation of hypertension in mice treated with uninephrectomy, angiotensin II (AngII), and a high-salt diet. We hypothesize that miR-204 in endothelial cells (EC) contributes to hypertension. We developed Mir204 fl/fl mice and crossed them with VE-Cadherin-Cre mice. The loss of miR-204 was confirmed in isolated endothelial cells (1 ± 0.15, 0.41 and 0.13 ± 0.05, fold in EC- Mir204 +/+ , EC- Mir204 +/- , and EC- Mir204 -/- mice, respectively; n=4, 1, and 4). AngII and 4% NaCl diet increased systolic blood pressure (SBP) by up to 40-50 mmHg in both male and female EC- Mir204 +/- and WT littermates (n=11 and 17). The SBP was significantly decreased by 20-30 mmHg in EC- Mir204 -/- mice (P 〈 0.05, n=10). Vascular function was assessed by pressure myograph in basilar artery following the Ang II and 4% NaCl diet treatment. In EC- Mir204 -/- male mice, the wall thickness (21.5 ± 0.1 vs 30 ± 3.1μm, n=7 and 2) and media/lumen ratio (0.2 ± 0.01 vs 0.51 ± 0.09, n=7 and 2) was significantly reduced compared with EC- Mir204 +/+ mice. Endothelial-dependent vasodilation (response to Ach) was lost in EC- Mir204 +/+ mice but largely preserved in EC- Mir204 -/- mice (P= 0.007). Renal interstitial fibrosis was not influenced by the miR-204 KO in endothelial cells (Cortex: 0.27 ± 0.04, 0.18 ± 0.01 %; Outer medulla: 0.18 ± 0.05, 0.19 ± 0.05 % in EC- Mir204 +/+ and EC- Mir204 -/- male mice, respectively; n=3 and 2). Urinary albumin excretion was increased during the two-week treatment. However, the albuminuria was not significantly affected by the knockout of miR-204 in endothelial cells (2.65 ± 1.13, 3.41 ± 0.86, and 2.86 ± 0.85 mg/24h in EC- Mir204 +/+ , EC- Mir204 +/- , and EC- Mir204 -/- mice, respectively; n=9, 11 and 6). Glomerular filtration rate did not differ among the three groups at baseline or study termination (Baseline: 188.3 ± 30.1, 223.1 ± 34.9, and 185.3 ± 21.3 μl/min, n=4, 2 and 5; Termination: 203.8 ± 22.1, 150.7 ± 30.3, and 193.9 ± 42.5 μl/min, n=6, 2 and 5 in EC- Mir204 +/+ , EC- Mir204 +/- , and EC- Mir204 -/- mice, respectively). The findings suggest that miR-204 in endothelial cells plays an important role in the development of hypertension associated with impaired endothelial-dependent vasodilation and vascular remodeling.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.79.suppl_1.P210
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 8
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    Role of DNA De Novo (De)Methylation in the Kidney in Salt-Induced Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Hypertension Vol. 72, No. 5 ( 2018-11), p. 1160-1171
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 72, No. 5 ( 2018-11), p. 1160-1171
    Abstract: Numerous adult diseases involving tissues consisting primarily of nondividing cells are associated with changes in DNA methylation. It suggests a pathophysiological role for de novo methylation or demethylation of DNA, which is catalyzed by DNA methyltransferase 3 and ten-eleven translocases. However, the contribution of DNA de novo (de)methylation to these diseases remains almost completely unproven. Broad changes in DNA methylation occurred within days in the renal outer medulla of Dahl SS rats fed a high-salt diet, a classic model of hypertension. Intrarenal administration of anti-DNA methyltransferase 3a/ten-eleven translocase 3 GapmeRs attenuated high salt-induced hypertension in SS rats. The high-salt diet induced differential expression of 1712 genes in the renal outer medulla. Remarkably, the differential expression of 76% of these genes was prevented by anti-DNA methyltransferase 3a/ten-eleven translocase 3 GapmeRs. The genes differentially expressed in response to the GapmeRs were involved in the regulation of metabolism and inflammation and were significantly enriched for genes showing differential methylation in response to the GapmeRs. These data indicate a significant role of DNA de novo (de)methylation in the kidney in the development of hypertension in SS rats. The findings should help to shift the paradigm of DNA methylation research in diseases involving nondividing cells from correlative analysis to functional and mechanistic studies.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.118.11650
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 9
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    Base-Resolution Maps of 5-Methylcytosine and 5-Hydroxymethylcytosine in Dahl S Rats : Effect of Salt and Genomic Sequence
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Hypertension Vol. 63, No. 4 ( 2014-04), p. 827-838
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 63, No. 4 ( 2014-04), p. 827-838
    Abstract: Analysis of 5-hydroxymethylcytosine (5hmC) at single-base resolution has been largely limited to studies of stem cells or developmental stages. Given the potential importance of epigenetic events in hypertension, we have analyzed 5hmC and 5-methylcytosine (5mC) at single-base resolution in the renal outer medulla of the Dahl salt-sensitive rat and examined the effect of disease-relevant genetic or environmental alterations on 5hmC and 5mC patterns. Of CpG sites that fell within CpG islands, 11% and 1% contained significant 5mC and 5hmC, respectively. 5mC levels were substantially higher for genes with lower mRNA abundance and showed a prominent nadir around the transcription start site. In contrast, 5hmC levels were higher in genes with higher expression. Substitution of a 12.9-Mbp region of chromosome 13, which attenuates the hypertensive and renal injury phenotypes in salt-sensitive rats, or exposure to a high-salt diet, which accelerates the disease phenotypes, was associated with differential 5mC or 5hmC in several hundred CpG islands. Nearly 80% of the CpG islands that were differentially methylated in response to salt and associated with differential mRNA abundance were intragenic CpG islands. The substituted genomic segment had significant cis effects on mRNA abundance but not on DNA methylation. The study established base-resolution maps of 5mC and 5hmC in an in vivo model of disease and revealed several characteristics of 5mC and 5hmC important for understanding the role of epigenetic modifications in the regulation of organ systems function and complex diseases.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.113.02637
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 10
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    Abstract P139: Stability of DNA Methylation Profiles in Human DNA Samples in Long Term Storage
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Hypertension Vol. 68, No. suppl_1 ( 2016-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 68, No. suppl_1 ( 2016-09)
    Abstract: Introductions: Historic DNA samples represent a potentially highly valuable resource for epigenetic analysis. Reduced representation bisulfite sequencing (RRBS) is a cost-effective, near genome-wide method for quantifying DNA methylation levels at single base resolution. It is unknown whether historic DNA samples stored for a long time (15-20 years) under various conditions could maintain stable methylation profiles as determined by RRBS. Methods: We used 5 groups of DNA samples (n=4 in each group) to compare and evaluate the stability of DNA methylation profiles under standard storage conditions of 4°C since 1996. Group 1 had been extracted from EDTA-anticoagulated blood and stored at 4°C since 1996; Group 2 had been diluted from group 1 to 10ng/μl and stored at -20°C since 2009; Group 3 were extracted from citrate-anticoagulated blood stored at -80°C since 1996; Group 4 were extracted from fresh EDTA-anticoagulated blood; Group 5 were extracted from fresh citrate-anticoagulated blood. The samples in groups 1, 2 and 3 were from the same subjects. All DNA samples were processed for RRBS libraries and then sequenced. Results: The global methylation level of group 1 was lower than group 2 (36.88±4.12% vs 43.66±1.29%, p=0.04), but was not statistically different from group 3 (44.31±1.46%, p=0.07). The methylation level of groups 4 and 5 (40.34±3.73% and 38.64±1.94%) was not significantly different. In addition, group 4 and 5 were not significantly different from group 1. The correlation of methylation levels for all CpG sites between individual samples in group 1 (0.987±0.001) was higher than that in group 2 and group 3 (0.984±0.002, p=0.01, and 0.969±0.015, p=0.01) and not significantly different from group 4 or 5. For CpG sites within CpG islands (CGI), the correlation between individual samples was not significantly different between any of the 5 groups. Moreover, the samples from the same subject show high correlation levels between groups 1, 2, and 3 for all CpG sites (0.987±0.006) and CpG sites within CGI (0.983±0.009). Conclusion: DNA samples stored at 4°C for prolonged periods of time are amenable to RRBS analysis. In addition, there were no significant differences in the DNA methylation profiles between citrate- and EDTA-anticoagulated blood.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.68.suppl_1.p139
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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