Epigenetic changes and alteration of<i>Fbn1</i>and<i>Col3A1</i>gene expression under hyperglycaemic and hyperinsulinaemic conditions

Gaikwad, Anil Bhanudas; Gupta, Jeena; Tikoo, Kulbhushan

doi:10.1042/bj20100414

Cited by 61 publications

(59 citation statements)

References 38 publications

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“…These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the complex pathogenesis of CVD and T2D. 26 …”

Section: Discussionsupporting

confidence: 73%

“…Forty-five of these genes have been implicated previously in CVD (24 genes) [24][25][26] and T2D (21 genes).…”

Section: Identification Of Biological Pathways Using Integrative Pathmentioning

confidence: 99%

“…Forty-five of these genes have been implicated previously in CVD (24 genes) [24][25][26] and T2D (21 genes). 14,27,28 Five of the 8 commonly enriched pathways, namely, HCM, dilated cardiomyopathy, ARVC, focal adhesion, and extracellular matrix-receptor interaction signaling, were also found to be highly interconnected as demonstrated by a shared common set of 117 genes among them ( Figure 1).…”

Section: Identification Of Biological Pathways Using Integrative Pathmentioning

confidence: 99%

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Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Chan

Huang

Meng

et al. 2014

Circ Cardiovasc Genet

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It has long been known that cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors and pathophysiological intermediaries including obesity, dyslipidemia, insulin resistance, and proinflammatory and prothrombotic states. [1][2][3] However, the key molecular drivers underlying these highly correlated phenotypes as well as the potential regulatory networks shared in the pathogenesis of CVD and T2D remain poorly understood. Clinical Perspective on p 919Of the ≈60 genetic loci identified for CVD and T2D in large-scale genome-wide association studies (GWAS), 5 only 2 significant loci (TCF7L2 and VEGFA) are shared between the 2 diseases. There are ≥3 fundamentally important questions that remain to be answered. First, are there additional genetic risks, either alone or concentrated in specific regulatory networks that may explain the pathophysiological connections between CVD and T2D? Second, are there any ethnicityspecific genetic mechanisms for these 2 common vascular diseases, given that there are drastic ethnicity-specific differences in their risk and linkage disequilibrium patterns. [6][7][8] Third, although common genetic loci have been detected across different populations (eg, the Chr9p21 locus for CVD and the TCF7L2 locus for T2D) supporting the presence of common pathological paths across ethnicity, to what degree molecular mechanisms are shared across ethnicities?To answer these 3 questions, we performed 2 GWAS for both CVD and T2D using an integrative pathway and network analysis in the national Women's Health Initiative SNP Health Association Resource (WHI-SHARe) and the Genomics and Background-Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. Methods and Results-Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. Conclusions-Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory ge...

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“…These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the complex pathogenesis of CVD and T2D. 26 …”

Section: Discussionsupporting

confidence: 73%

“…Forty-five of these genes have been implicated previously in CVD (24 genes) [24][25][26] and T2D (21 genes).…”

Section: Identification Of Biological Pathways Using Integrative Pathmentioning

confidence: 99%

Section: Identification Of Biological Pathways Using Integrative Pathmentioning

confidence: 99%

See 1 more Smart Citation

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Chan

Huang

Meng

et al. 2014

Circ Cardiovasc Genet

View full text Add to dashboard Cite

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“…Reports showed that kidneys from diabetic animals exhibit changes in global histone PTMs as well as H3KAc at the fibrillin 1 promoter and that HDAC-2 may mediate ECM accumulation and epithelial-to-mesenchymal transition in the diabetic kidney and in TGF-␤1-treated epithelial cells (14,37). We recently demonstrated that TGF-␤1-induced profibrotic gene expression in MCs was associated with specific alterations in the levels of key active and repressive histone lysine methylation marks at their promoters (51).…”

Section: ␤1mentioning

confidence: 99%

Involvement of p300/CBP and epigenetic histone acetylation in TGF-β1-mediated gene transcription in mesangial cells

Yuan

Reddy

Sun

et al. 2013

American Journal of Physiology-Renal Physiology

131

119

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Transforming growth factor-β1 (TGF-β1)-induced expression of plasminogen activator inhibitor-1 (PAI-1) and p21 in renal mesangial cells (MCs) plays a major role in glomerulosclerosis and hypertrophy, key events in the pathogenesis of diabetic nephropathy. However, the involvement of histone acetyl transferases (HATs) and histone deacetylases (HDACs) that regulate epigenetic histone lysine acetylation, and their interaction with TGF-β1-responsive transcription factors, are not clear. We evaluated the roles of histone acetylation, specific HATs, and HDACs in TGF-β1-induced gene expression in rat mesangial cells (RMCs) and in glomeruli from diabetic mice. Overexpression of HATs CREB binding protein (CBP) or p300, but not p300/CBP-activating factor, significantly enhanced TGF-β1-induced PAI-1 and p21 mRNA levels as well as transactivation of their promoters in RMCs. Conversely, they were significantly attenuated by HAT domain mutants of CBP and p300 or overexpression of HDAC-1 and HDAC-5. Chromatin immunoprecipitation assays showed that TGF-β1 treatment led to a time-dependent enrichment of histone H3-lysine9/14-acetylation (H3K9/14Ac) and p300/CBP occupancies around Smad and Sp1 binding sites at the PAI-1 and p21 promoters. TGF-β1 also enhanced the interaction of p300 with Smad2/3 and Sp1 and increased Smad2/3 acetylation. High glucose-treated RMCs exhibited increased PAI-1 and p21 levels, and promoter H3K9/14Ac, which were blocked by TGF-β1 antibodies. Furthermore, increased PAI-1 and p21 expression was associated with elevated promoter H3K9/14Ac levels in glomeruli from diabetic mice. Thus TGF-β1-induced PAI-1 and p21 expression involves interaction of p300/CBP with Smads and Sp1, and increased promoter access via p300/CBP-induced H3K9/14Ac. This in turn can augment glomerular dysfunction linked to diabetic nephropathy.

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“…HDAC2, 4 and 5 were upregulated in streptozotocin-induced diabetic nephropathy, db/db mouse models, and diabetic patient kidney biopsies [20,21]. HDAC-2 mediated extracellular matrix accumulation and epithelial-to-mesenchymal transition in the diabetic kidney and in TGF-β1-treated epithelial cells [22,23]. HDAC inhibitors, including Trichostatin A (TSA), have been reported to attenuate diabetic nephropathy [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

High glucose induces inflammatory reactions and changes in histonemodifying enzymes in rat mesangial cells

Lee¹,

Lee²,

Jo³

et al. 2018

biomedicalresearch

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Epigenetic changes and alteration ofFbn1andCol3A1gene expression under hyperglycaemic and hyperinsulinaemic conditions

Cited by 61 publications

References 38 publications

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Involvement of p300/CBP and epigenetic histone acetylation in TGF-β1-mediated gene transcription in mesangial cells

High glucose induces inflammatory reactions and changes in histonemodifying enzymes in rat mesangial cells

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