Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics
- Rowland, Joshua, Akbarov, Artur, Eales, James, Xu, Xiaoguang, Dormer, John, Guo, Hui, Denniff, Matthew, Jiang, Xiao, Ranjzad, Parisa, Nazgiewicz, Alicja, Prestes, Priscilla, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Zukowska-Szczechowska, Ewa, Bogdanski, Pawel, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
- Full Text:
- Reviewed:
- Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
- Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
- Full Text:
- Reviewed:
- Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
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
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