Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise
- Denham, Joshua, O'Brien, Brendan, Marques, Francine, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 118, no. 4 (2015), p. 475-488
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Physical exercise has proven cardiovascular benefits, yet there is no clear understanding of the related molecular mechanisms leading to this. Here we determined the beneficial epigenetic effects of exercise after sprint interval training, a form of exercise known to improve cardiometabolic health. We quantified genome-wide leukocyte DNA methylation of 12 healthy young (18-24 yr) men before and after 4 wk (thrice weekly) of sprint interval training using the 450K BeadChip (Illumina) and validated gene expression changes in an extra seven subjects. Exercise increased subjects' cardiorespiratory fitness and maximal running performance, and decreased low-density lipoprotein cholesterol concentration in conjunction with genome-wide DNA methylation changes. Notably, many CpG island and gene promoter regions were demethylated after exercise, indicating increased genome-wide transcriptional changes. Among genes with DNA methylation changes, epidermal growth factor (EGF), a ligand of the epidermal growth factor receptor known to be involved in cardiovascular disease, was demethylated and showed decreased mRNA expression. Additionally, we found that in microRNAs miR-21 and miR-210, gene DNA methylation was altered by exercise causing a cascade effect on the expression of the mature microRNA involved in cardiovascular function. Our findings demonstrate that exercise alters DNA methylation in circulating blood cells in microRNA and protein-coding genes associated with cardiovascular physiology. Copyright © 2015 the American Physiological Society
Epigenetic modifications in essential hypertension
- Wise, Ingrid, Charchar, Fadi
- Authors: Wise, Ingrid , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 17, no. 4 (2016), p. 1-14
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world’s leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development. © 2016 by the authors; licensee MDPI, Basel, Switzerland.
- Authors: Wise, Ingrid , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 17, no. 4 (2016), p. 1-14
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world’s leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development. © 2016 by the authors; licensee MDPI, Basel, Switzerland.
Neurogenic hypertension : Revelations from genome-wide gene expression profiling
- Marques, Francine, Morris, Brian
- Authors: Marques, Francine , Morris, Brian
- Date: 2012
- Type: Text , Journal article
- Relation: Current Hypertension Reports Vol. 14, no. 6 (2012), p. 485-491
- Full Text: false
- Reviewed:
- Description: There is now good evidence for a role of the sympathetic nervous system in the etiology of essential hypertension in humans. Although genetic variation is expected to underlie the elevated sympathetic outflow in this complex polygenic condition, only limited information has emerged from classic molecular genetic studies. Recently, progress has been made in understanding neurogenic aspects by determination of global alterations in gene expression in key brain regions of animal models of neurogenic hypertension. Such genome-wide expression studies in the hypothalamus and brainstem support roles for factors such as neuronal nitric oxide synthase, inflammation and reactive oxygen species. A role for non-coding RNAs such as microRNAs, and epigenetic alterations await exploration. Ongoing novel approaches should provide a better understanding of the processes responsible for the increased sympathetic outflow in animal models, as well as essential hypertension in humans. Such information may lead to better therapies for neurogenic hypertension in humans. © Springer Science+Business Media, LLC 2012.
- Description: 2003010573
Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans
- Denham, Joshua, O'Brien, Brendan, Harvey, Jack, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Harvey, Jack , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Epigenomics Vol. 7, no. 5 (2015), p. 717-731
- Full Text:
- Reviewed:
- Description: Aim: DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation. Materials & methods: Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina). Results: Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson's disease. Conclusions: Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.
- Authors: Denham, Joshua , O'Brien, Brendan , Harvey, Jack , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Epigenomics Vol. 7, no. 5 (2015), p. 717-731
- Full Text:
- Reviewed:
- Description: Aim: DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation. Materials & methods: Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina). Results: Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson's disease. Conclusions: Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.
Muscle-enriched MicroRNAs isolated from whole blood are regulated by exercise and are potential biomarkers of cardiorespiratory fitness
- Denham, Joshua, Prestes, Priscilla
- Authors: Denham, Joshua , Prestes, Priscilla
- Date: 2016
- Type: Text , Journal article
- Relation: Frontiers in Genetics Vol. 7, no. NOV (2016), p. 1-8
- Full Text:
- Reviewed:
- Description: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally. Evidence indicating miRNAs influence exercise-induced health and performance adaptations is mounting. Circulating miRNAs are responsible for intercellular communication and could serve as biomarkers for disease and exercise-related traits. Such biomarkers would contribute to exercise screening, monitoring, and the development of personalized exercise prescription. Accordingly, we investigated the impact of long-term strenuous aerobic exercise training and a single bout of maximal aerobic exercise on five muscle-enriched miRNAs implicated in exercise adaptations (miR-1, miR-133a, miR-181a, miR-486, and miR-494). We also determined linear correlations between miRNAs, resting heart rate, and maximum oxygen uptake (V˙O2 max). We used TaqMan assay quantitative polymerase chain reaction to analyze the abundance of miR-1, miR-133a, miR-181a, miR-486, and miR-494 in resting whole blood of 67 endurance athletes and 61 healthy controls. Relative to controls, endurance athletes exhibited increased miR-1, miR-486, and miR-494 content (1.26- to 1.58-fold change, all p < 0.05). miR-1, miR-133a, and miR-486 were decreased immediately after maximal aerobic exercise (0.64- to 0.76-fold change, all p < 0.01) performed by 19 healthy, young men (20.7 ± 2.4 years). Finally, we observed positive correlations between miRNA abundance and V˙ O2 max (miR-1 and miR-486) and an inverse correlation between miR-486 and resting heart rate. Therefore, muscle-enriched miRNAs isolated from whole blood are regulated by acute and long-term aerobic exercise training and could serve as biomarkers of cardiorespiratory fitness. © 2016 Denham and Prestes.
- Authors: Denham, Joshua , Prestes, Priscilla
- Date: 2016
- Type: Text , Journal article
- Relation: Frontiers in Genetics Vol. 7, no. NOV (2016), p. 1-8
- Full Text:
- Reviewed:
- Description: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally. Evidence indicating miRNAs influence exercise-induced health and performance adaptations is mounting. Circulating miRNAs are responsible for intercellular communication and could serve as biomarkers for disease and exercise-related traits. Such biomarkers would contribute to exercise screening, monitoring, and the development of personalized exercise prescription. Accordingly, we investigated the impact of long-term strenuous aerobic exercise training and a single bout of maximal aerobic exercise on five muscle-enriched miRNAs implicated in exercise adaptations (miR-1, miR-133a, miR-181a, miR-486, and miR-494). We also determined linear correlations between miRNAs, resting heart rate, and maximum oxygen uptake (V˙O2 max). We used TaqMan assay quantitative polymerase chain reaction to analyze the abundance of miR-1, miR-133a, miR-181a, miR-486, and miR-494 in resting whole blood of 67 endurance athletes and 61 healthy controls. Relative to controls, endurance athletes exhibited increased miR-1, miR-486, and miR-494 content (1.26- to 1.58-fold change, all p < 0.05). miR-1, miR-133a, and miR-486 were decreased immediately after maximal aerobic exercise (0.64- to 0.76-fold change, all p < 0.01) performed by 19 healthy, young men (20.7 ± 2.4 years). Finally, we observed positive correlations between miRNA abundance and V˙ O2 max (miR-1 and miR-486) and an inverse correlation between miR-486 and resting heart rate. Therefore, muscle-enriched miRNAs isolated from whole blood are regulated by acute and long-term aerobic exercise training and could serve as biomarkers of cardiorespiratory fitness. © 2016 Denham and Prestes.
Epigenetic modifications in essential hypertension
- Authors: Wise, Ingrid
- Date: 2018
- Type: Text , Thesis , PhD
- Full Text:
- Description: Background: Hypertension (HTN) is a complex, multifactorial, quantitative trait under polygenic control that affects more than one billion people globally. Despite advances in our understanding of the pathophysiology of HTN and the implementation of more effective treatment and prevention strategies, HTN remains one of the world’s great public health problems. The accepted inference from genome-wide association studies (GWAS) is that the genetic code lays the foundation for transcriptomic changes and in turn physiological change. On the other side of the coin, environmental factors (smoking, diet, chemical exposure) can in turn affect DNA itself in genes relevant to blood pressure (BP). Variation in epigenetic forms of modification may thus explain additional phenotypic variation in BP and provide new clues to the physiological processes influencing its regulation. DNA methylation is one of these epigenetic mechanisms responsible for changes to gene expression, activated by interaction with environmental triggers. DNA methylation is a reversible epigenetic modifier of specific dinucleotide sites called CpGs, which consists of a transfer of a methyl group derived from S-adenosyl-L-methionine to position five of a cytosine ring, forming 5mC. Pathophysiologically, the kidney is known as the key organ of BP regulation and one of the most important contributors to HTN. According to the hypothesis put forward by Guyton, over 40 years ago, the control of BP in the steady-state and longer-term is critically dependent on renal mechanisms. In fact, almost all monogenic forms of HTN are driven by rare mutations in genes involved in salt handling in the distal nephron. It is therefore crucial to understand kidney DNA methylation changes that may drive gene expression in kidney and lead to HTN. Hypothesis: The central hypothesis underpinning this PhD thesis is that alterations in kidney specific DNA methylation plays a fundamental role in modulating gene expression changes involved in the regulation of BP and pathophysiology of EH. Aims: This PhD thesis focuses on characterising the role of DNA methylation in the hypertensive kidney using array and RNA-sequencing methods. Three major aims are addressed: • Aim 1: To characterise blood and kidney global DNA methylation dynamics and its functional role in the hypertensive population (Chapter 3). • Aim 2: To determine the role of genome-wide, loci specific DNA methylation in the hypertensive human kidney (Chapter 4). • Aim 3: To understand the relationship between DNA methylation and differential expression of genes associated with BP and HTN in the human kidney (Chapter 5). Results: In Aim 1 global DNA methylation changes were characterised in peripheral blood leukocyte and kidney DNA of the hypertensive (HT) population using he ELISA method. We found no association between HTN diagnosis and global methylation percentage in either peripheral blood leukocytes or kidney DNA. However, a negative correlation was found between global methylation and diastolic blood pressure (DBP), yet this relationship was not evident after adjustment for the effect of antihypertensive medication. Furthermore, we investigated the sensitivity of ELISA-based global methylation detection by calculating the percentage of global methylation in kidney using array based methods; the results were similar, demonstrating no association between HTN diagnosis and median kidney methylation
- Description: Doctor of Philosophy
- Authors: Wise, Ingrid
- Date: 2018
- Type: Text , Thesis , PhD
- Full Text:
- Description: Background: Hypertension (HTN) is a complex, multifactorial, quantitative trait under polygenic control that affects more than one billion people globally. Despite advances in our understanding of the pathophysiology of HTN and the implementation of more effective treatment and prevention strategies, HTN remains one of the world’s great public health problems. The accepted inference from genome-wide association studies (GWAS) is that the genetic code lays the foundation for transcriptomic changes and in turn physiological change. On the other side of the coin, environmental factors (smoking, diet, chemical exposure) can in turn affect DNA itself in genes relevant to blood pressure (BP). Variation in epigenetic forms of modification may thus explain additional phenotypic variation in BP and provide new clues to the physiological processes influencing its regulation. DNA methylation is one of these epigenetic mechanisms responsible for changes to gene expression, activated by interaction with environmental triggers. DNA methylation is a reversible epigenetic modifier of specific dinucleotide sites called CpGs, which consists of a transfer of a methyl group derived from S-adenosyl-L-methionine to position five of a cytosine ring, forming 5mC. Pathophysiologically, the kidney is known as the key organ of BP regulation and one of the most important contributors to HTN. According to the hypothesis put forward by Guyton, over 40 years ago, the control of BP in the steady-state and longer-term is critically dependent on renal mechanisms. In fact, almost all monogenic forms of HTN are driven by rare mutations in genes involved in salt handling in the distal nephron. It is therefore crucial to understand kidney DNA methylation changes that may drive gene expression in kidney and lead to HTN. Hypothesis: The central hypothesis underpinning this PhD thesis is that alterations in kidney specific DNA methylation plays a fundamental role in modulating gene expression changes involved in the regulation of BP and pathophysiology of EH. Aims: This PhD thesis focuses on characterising the role of DNA methylation in the hypertensive kidney using array and RNA-sequencing methods. Three major aims are addressed: • Aim 1: To characterise blood and kidney global DNA methylation dynamics and its functional role in the hypertensive population (Chapter 3). • Aim 2: To determine the role of genome-wide, loci specific DNA methylation in the hypertensive human kidney (Chapter 4). • Aim 3: To understand the relationship between DNA methylation and differential expression of genes associated with BP and HTN in the human kidney (Chapter 5). Results: In Aim 1 global DNA methylation changes were characterised in peripheral blood leukocyte and kidney DNA of the hypertensive (HT) population using he ELISA method. We found no association between HTN diagnosis and global methylation percentage in either peripheral blood leukocytes or kidney DNA. However, a negative correlation was found between global methylation and diastolic blood pressure (DBP), yet this relationship was not evident after adjustment for the effect of antihypertensive medication. Furthermore, we investigated the sensitivity of ELISA-based global methylation detection by calculating the percentage of global methylation in kidney using array based methods; the results were similar, demonstrating no association between HTN diagnosis and median kidney methylation
- Description: Doctor of Philosophy
Delayed self-regulation and time-dependent chemical drive leads to novel states in epigenetic landscapes
- Mitra, Mitra, Taylor, Paul, Hutchison, Chris, McLeish, T. C. B., Chakrabarti, Buddapriya
- Authors: Mitra, Mitra , Taylor, Paul , Hutchison, Chris , McLeish, T. C. B. , Chakrabarti, Buddapriya
- Date: 2014
- Type: Text , Journal article
- Relation: Journal of the Royal Society Interface Vol. 11, no. 100 (2014), p.
- Full Text:
- Reviewed:
- Description: The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represent their undifferentiated and differentiated states, respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far.We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single-gene regulatory circuit.We show that the interplay of time-dependent drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells.We also comment on howsuch an oscillatory state can provide a framework for understanding more general feedback circuits in cell development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
- Description: The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represent their undifferentiated and differentiated states, respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far.We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single-gene regulatory circuit.We showthat the interplay of time-dependent drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells.We also comment on howsuch an oscillatory state can provide a framework for understanding more general feedback circuits in cell development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
- Authors: Mitra, Mitra , Taylor, Paul , Hutchison, Chris , McLeish, T. C. B. , Chakrabarti, Buddapriya
- Date: 2014
- Type: Text , Journal article
- Relation: Journal of the Royal Society Interface Vol. 11, no. 100 (2014), p.
- Full Text:
- Reviewed:
- Description: The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represent their undifferentiated and differentiated states, respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far.We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single-gene regulatory circuit.We show that the interplay of time-dependent drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells.We also comment on howsuch an oscillatory state can provide a framework for understanding more general feedback circuits in cell development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
- Description: The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represent their undifferentiated and differentiated states, respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far.We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single-gene regulatory circuit.We showthat the interplay of time-dependent drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells.We also comment on howsuch an oscillatory state can provide a framework for understanding more general feedback circuits in cell development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
Wnt signaling pathway inhibitor Sclerostin inhibits angiotensin II-induced aortic aneurysm and atherosclerosis
- Krishna, Smriti, Seto, Sai-Wang, Jose, Roby, Li, Jiaze, Morton, Susan, Biros, Erik, Wang, Yutang, Nsengiyumva, Vianne, Lindeman, Jan, Loots, Gabriela, Rush, Catherine, Craig, Jeffrey, Golledge, Jonathan
- Authors: Krishna, Smriti , Seto, Sai-Wang , Jose, Roby , Li, Jiaze , Morton, Susan , Biros, Erik , Wang, Yutang , Nsengiyumva, Vianne , Lindeman, Jan , Loots, Gabriela , Rush, Catherine , Craig, Jeffrey , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Arteriosclerosis Thrombosis and Vascular Biology Vol. 37, no. 3 (2017), p. 553-566
- Full Text:
- Reviewed:
- Description: Objective-Sclerostin (SOST) has been identified as an important regulator of bone formation; however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human samples, a mouse model, and in vitro investigations. Approach and Results-SOST protein was downregulated in human and mouse AA samples compared with controls. Transgenic introduction of human SOST in apolipoprotein E-deficient (ApoE(-/-)) mice (SOSTTg. ApoE(-/-)) and administration of recombinant mouse Sost inhibited angiotensin II-induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOSTTg. ApoE(-/-) mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOSTTg. ApoE(-/-) mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/beta-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOSTTg. ApoE(-/-) mice. SOST expression was downregulated and the winglesstype mouse mammary virus integration site/beta-catenin pathway was activated in human AA samples. The cytosinephosphate- guanine islands in the SOST gene promoter showed significantly higher methylation in human AA samples compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated. Conclusions-This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.
- Authors: Krishna, Smriti , Seto, Sai-Wang , Jose, Roby , Li, Jiaze , Morton, Susan , Biros, Erik , Wang, Yutang , Nsengiyumva, Vianne , Lindeman, Jan , Loots, Gabriela , Rush, Catherine , Craig, Jeffrey , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Arteriosclerosis Thrombosis and Vascular Biology Vol. 37, no. 3 (2017), p. 553-566
- Full Text:
- Reviewed:
- Description: Objective-Sclerostin (SOST) has been identified as an important regulator of bone formation; however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human samples, a mouse model, and in vitro investigations. Approach and Results-SOST protein was downregulated in human and mouse AA samples compared with controls. Transgenic introduction of human SOST in apolipoprotein E-deficient (ApoE(-/-)) mice (SOSTTg. ApoE(-/-)) and administration of recombinant mouse Sost inhibited angiotensin II-induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOSTTg. ApoE(-/-) mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOSTTg. ApoE(-/-) mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/beta-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOSTTg. ApoE(-/-) mice. SOST expression was downregulated and the winglesstype mouse mammary virus integration site/beta-catenin pathway was activated in human AA samples. The cytosinephosphate- guanine islands in the SOST gene promoter showed significantly higher methylation in human AA samples compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated. Conclusions-This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.
Genetic and epigenetic changes associated with polygenic left ventricular hypertrophy
- Authors: Prestes, Priscilla
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.
- Description: Doctor of Philosophy
- Authors: Prestes, Priscilla
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.
- Description: Doctor of Philosophy
Exercise, epigenetics, and aging
- Chilton, Warrick, Maier, Maier, Akinnibosun, Olutope, O’Brien, Brendan, Charchar, Fadi
- Authors: Chilton, Warrick , Maier, Maier , Akinnibosun, Olutope , O’Brien, Brendan , Charchar, Fadi
- Date: 2021
- Type: Text , Book chapter
- Relation: Epigenetics of Exercise and Sports: Concepts, Methods, and Current Research Chapter 27 p. 127-182
- Full Text: false
- Reviewed:
- Description: This chapter introduces the epigenetic processes that govern how exercise affects the aging processes. We begin with an introduction to the molecular changes that occur with aging including methylation and histone and noncoding RNA modifications. We then present the evidence for changes in these processes by exercise and physical activity, Lastly, we present evidence for and against a role for exercise on changes in telomere length and aging. © 2021 Elsevier Inc. All rights reserved.
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