Digital Commons Network^™

A High-Fat Diet Alters Genome-Wide Dna Methylation And Gene Expression In Sm/J Mice, Madeline R. Keleher, Rabab Zaidi, Lauren Hicks, Shyam Shah, Xiaoyun Xing, Daofeng Li, Ting Wang, James M. Cheverud

Biology: Faculty Publications and Other Works

Background: While the genetics of obesity has been well defined, the epigenetics of obesity is poorly understood. Here, we used a genome-wide approach to identify genes with differences in both DNA methylation and expression associated with a high-fat diet in mice. Results: We weaned genetically identical Small (SM/J) mice onto a high-fat or low-fat diet and measured their weights weekly, tested their glucose and insulin tolerance, assessed serum biomarkers, and weighed their organs at necropsy. We measured liver gene expression with RNA-seq (using 21 total libraries, each pooled with 2 mice of the same sex and diet) and DNA methylation …

Dna Methylation By Restriction Modification Systems Affects The Global Transcriptome Profile In Borrelia Burgdorferi, Timothey Casselli, Yvonne Tourand, Adam Scheidegger, William K. Arnold, Anna Proulx, Brian Stevenson, Catherine A. Brissette

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Prokaryote restriction modification (RM) systems serve to protect bacteria from potentially detrimental foreign DNA. Recent evidence suggests that DNA methylation by the methyltransferase (MTase) components of RM systems can also have effects on transcriptome profiles. The type strain of the causative agent of Lyme disease, Borrelia burgdorferi B31, possesses two RM systems with N6-methyladenosine (m6A) MTase activity, which are encoded by the bbe02 gene located on linear plasmid lp25 and bbq67 on lp56. The specific recognition and/or methylation sequences had not been identified for either of these B. burgdorferi MTases, and it was not previously known whether these RM …

Innate Immune Cell Phenotypes Are Dictated By Distinct Epigenetic Reprogramming, Kevin Douglas Adams

Theses and Dissertations

The innate immune system is the first line of host defense against external exposures. During these initial encounters, antigen presenting cells - specifically monocytes and macrophages - modulate further inflammatory responses. Macrophages exist along a spectrum of phenotypic programs; on the inflammatory M1 end they enhance immune activity while on the anti-inflammatory M2 end they suppress further immune activation. Furthermore, within M2 macrophages there exist many subpopulations, namely M2a and M2d, each with specific roles during infection or exposure. We sought to compare the epigenetic profiles of these subpopulations of macrophages to determine key regulatory gene networks and factors that …

Role Of P300 Zz Domain In Chromatin Association And Histone Acetylation, Yongming Xue

Dissertations & Theses (Open Access)

Transcription is strictly regulated by numerous factors including transcription coactivators. The p300 protein and its close paralogue CREB-binding protein (CREBBP, aka CBP) are well-known transcriptional coactivators that have intrinsic lysine acetyltransferase activity. The functions of p300/CBP largely rely on their capabilities to bind to chromatin and to acetylate the histone substrates. However, the molecular mechanisms underlying the regulation of these processes are not fully understood.

Through combination of various biochemical, biophysical and molecular approaches, we show that the ZZ-type zinc finger (ZZ) domain of p300 functions as a histone reader that specifically binds the N-terminal tail of histone H3. Crystal …

Genetic And Epigenetic Investigations On Pulmonary Hypertension Syndrome In Meat Type- Chickens, Khaloud Alzahrani

Graduate Theses and Dissertations

This dissertation presents a collection of studies that investigate the genetic and epigenetic associations to ascites phenotype in broiler chickens. Ascites is a significant metabolic disease associated with fast-growing meat-type chickens (broilers) and is a terminal result of pulmonary hypertension syndrome PHS. It is a multi-factorial syndrome caused by interactions between genetic, physiological, environmental, and managemental factors. It was estimated that ascites accounts for losses of about US$1 billion annually worldwide and for over 25% of broilers mortality. Although traditional and molecular genetic methods in the selection and in performance improvements, has greatly reduced ascites frequency, yet it has not …

Epigenetic Mechanisms Regulating The Functional Effects Of Chronic Alcohol Exposure Of Human Monocyte-Derived Dendritic Cells, Tiyash Parira

FIU Electronic Theses and Dissertations

The effects of alcohol abuse are multi-dimensional since alcohol is widely known to affect both the innate and adaptive immune systems. Recently, epigenetics has come into focus and has been implicated in many diseases as well as substance abuse disorders. Therefore, research efforts of understanding the epigenetic mechanisms underlying substance abuse effects including alcohol abuse have become more predominant.

In our laboratory, we have studied different epigenetic changes induced by alcohol exposure including regulation of histone deacetylases (HDACs), histone quantity, and histone modifications such as acetylation and deacetylation. We have observed differential effects of acute and chronic alcohol exposure in …

Application Of Novel And Existing Methods To Identify Genes With Evidence Of Epigenetic Association: Results From Gaw20, Angga M. Fuady, Samantha Lent, Chloé Sarnowski, Nathan L. Tintle

Faculty Work Comprehensive List

Background: The rise in popularity and accessibility of DNA methylation data to evaluate epigenetic associations with disease has led to numerous methodological questions. As part of GAW20, our working group of 8 research groups focused on gene searching methods.

Results: Although the methods were varied, we identified 3 main themes within our group. First, many groups tackled the question of how best to use pedigree information in downstream analyses, finding that (a) the use of kinship matrices is common practice, (b) ascertainment corrections may be necessary, and (c) pedigree information may be useful for identifying parent-of-origin effects. Second, many groups …

Gaw20: Methods And Strategies For The New Frontiers Of Epigenetics And Pharmacogenomics, Nathan L. Tintle, David W. Fardo, Marzia De Andrade, Stella Aslibekyan, Julia N. Bailey, Justo Lorenzo Bermejo, Rita M. Cantor, Saurabh Ghosh, Philip Melton, Xuexua Wang, Jean W. Maccluer, Laura Almasy

Biostatistics Faculty Publications

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual …

Epigenome Wide Association Study Of Snp–Cpg Interactions On Changes In Triglyceride Levels After Pharmaceutical Intervention: A Gaw20 Analysis, Jenna Veenstra, Anya Kalsbeek, Karissa Koster, Nathan Ryder, Abbey Bos, Jordan Huisman, Lucas Vander Berg, Jason Vander Woude, Nathan L. Tintle

Faculty Work Comprehensive List

In the search for an understanding of how genetic variation contributes to the heritability of common human disease, the potential role of epigenetic factors, such as methylation, is being explored with increasing frequency. Although standard analyses test for associations between methylation levels at individual cytosine-phosphateguanine (CpG) sites and phenotypes of interest, some investigators have begun testing for methylation and how methylation may modulate the effects of genetic polymorphisms on phenotypes. In our analysis, we used both a genome-wide and candidate gene approach to investigate potential single-nucleotide polymorphism (SNP)–CpG interactions on changes in triglyceride levels. Although we were able to identify …

Longitudinal Data Methods For Evaluating Genome-By-Epigenome Interactions In Families, Justin C. Strickland, I-Chen Chen, Chanung Wang, David W. Fardo

Psychology Faculty Publications

Background: Longitudinal measurement is commonly employed in health research and provides numerous benefits for understanding disease and trait progression over time. More broadly, it allows for proper treatment of correlated responses within clusters. We evaluated 3 methods for analyzing genome-by-epigenome interactions with longitudinal outcomes from family data.

Results: Linear mixed-effect models, generalized estimating equations, and quadratic inference functions were used to test a pharmacoepigenetic effect in 200 simulated posttreatment replicates. Adjustment for baseline outcome provided greater power and more accurate control of Type I error rates than computation of a pre-to-post change score.

Conclusions: Comparison of all modeling approaches indicated …

Hypermethylation Of Mir21 In Cd4+ T Cells From Patients With Relapsing-Remitting Multiple Sclerosis Associates With Lower Mirna-21 Levels And Concomitant Up-Regulation Of Its Target Genes, Sabrina Ruhrmann, Ewoud Ewing, Eliane Piket, Lara Kular, Julio Cesar Cetrulo Lorenzi, Sunjay Jude Fernandes, Hiromasa Morikawa, Shahin Aeinehband, Sergi Sayols-Baixeras, Stella Aslibekyan, Devin M. Absher, Donna K. Arnett, Jesper Tegner, David Gomez-Cabrero, Fredrik Piehl, Maja Jagodic

Epidemiology and Environmental Health Faculty Publications

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic and environmental risk factors.

Objective: We sought to identify DNA methylation changes in CD4+ T cells in patients with relapsing-remitting (RR-MS) and secondary-progressive (SP-MS) disease and healthy controls (HC).

Methods: We performed DNA methylation analysis in CD4+ T cells from RR-MS, SP-MS, and HC and associated identified changes with the nearby risk allele, smoking, age, and gene expression.

Results: We observed significant methylation differences in …

Aged Murine Hematopoietic Stem Cells Drive Aging-Associate Immune Remodeling, Hanna Leins, Medhanie Mulaw, Karina Eiwen, Vadim Sakk, Ying Liang, Michael Denkinger, Hartmut Geiger, Reinhold Schirmbeck

Toxicology and Cancer Biology Faculty Publications

Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN. To study the quality of immune systems …

Targeted Epigenetic Editing Using Optogenetic Tools, Joshua Hahn, Chongli Yuan

The Summer Undergraduate Research Fellowship (SURF) Symposium

Epigenetics markers, such as DNA methylation and histone post-translational modifications, are modifications to the structure of DNA that impact gene expression without altering the genetic code. Among them, DNA methylation plays a critical role in various biological processes including the differentiation of stem cells, regulation of gene expression, and adaptation to environmental signals. The ability to modify DNA methylation at particular genes in various cell types is thus desirable for engineering specific cell phenotypes. Although technologies exist that can alter DNA methylation at target genes, these techniques lack spatial and temporal resolution and are not able to selectively edit individual …

Twisted Tales: Insights Into Genome Diversity Of Ciliates Using Single-Cell ‘Omics, Maurer-Alcala X. Xyrus X. Maurer-Alcala, Ying Yan, Olivia A. Pilling, Rob Knight, Laura A. Katz

Biological Sciences: Faculty Publications

The emergence of robust single-cell ‘omics techniques enables studies of uncultivable species, allowing for the (re)discovery of diverse genomic features. In this study, we combine single-cell genomics and transcriptomics to explore genome evolution in ciliates (a > 1 Gy old clade). Analysis of the data resulting from these single-cell ‘omics approaches show: 1) the description of the ciliates in the class Karyorelictea as “primitive”is inaccurate because their somatic macronuclei contain loci of varying copy number (i.e., they have been processed by genome rearrangements from the zygotic nucleus); 2) gene-sized somatic chromosomes exist in the class Litostomatea, consistent with Balbiani’s (1890) observation …

Continuous Environmental Tracking: An Engineering Framework To Understand Adaptation And Diversification, Randy J. Guliuzza, Phil Gaskill

Proceedings of the International Conference on Creationism

We offer a new framework for understanding biological adaptability based on interpreting the findings of 342 journal articles and 67 online reports related to adaptation, bioengineering, and design in view of the assumption that biological functions are most accurately explained by engineering principles. We hypothesize that organisms actively and continuously track environmental variables and respond by self-adjusting to changing environments—utilizing the engineering principles constraining how human-designed objects self-adjust to changes—which results in adaptation. We termed this hypothesis Continuous Environmental Tracking (CET). CET is an engineering-based, organism-focused characterization of adaptation. CET expects to find that organisms adapt via systems with elements …

The Search For A Hero Gene: Fact Or Fiction?, Olivia Efthimiou

Heroism Science

The radical entry of heroism research into scientific inquiry presents interesting challenges and possibilities for the study of heroism and the human condition more broadly. This ‘final frontier’ of the enduring phenomenon of heroism stands to offer remarkable, unprecedented, and controversial advances in our understanding of heroic and human behaviour. Is a genetic basis for heroism a real possibility? If so, what would its impacts be? Advances in genomics and increased interest in the fields of epigenetics and neuroplasticity might hold the key to its discovery. This article considers some of the leading emerging research in global health genomics and …

Impact Of Bodyweight On Tissue-Specific Folate Status, Genome Wide And Gene-Specific Dna Methylation In Normal Breast Tissues From Premenopausal Women, Armina-Lyn Frederick

Masters Theses

Obesity has reached an epidemic level in the United States. A number of epidemiological studies have established obesity as a critical risk factor for postmenopausal breast cancer (post-BC), whereas a reverse association holds prior to menopause. A significant scientific gap exists in understanding the mechanism(s) underpinning this epidemiological phenomenon, particularly the reverse association between obesity and premenopausal breast cancer (pre-BC). This study aimed to understand how folate metabolism and DNA methylation informs the association between obesity and pre-BC. Fifty normal breast tissue samples were collected from premenopausal women who underwent reduction mammoplasty. We developed and measured the breast tissue folate …

Salt Stress Induces Non-Cg Methylation In Coding Regions Of Barley Seedlings (Hordeum Vulgare), Moumouni Konate, Michael J. Wilkinson, Benjamin T. Mayne, Stephen M. Pederson, Eileen S. Scott, Bettina Berger, Carlos M. Rodriguez Lopez

Horticulture Faculty Publications

Salinity can negatively impact crop growth and yield. Changes in DNA methylation are known to occur when plants are challenged by stress and have been associated with the regulation of stress-response genes. However, the role of DNA-methylation in moderating gene expression in response to salt stress has been relatively poorly studied among crops such as barley. Here, we assessed the extent of salt-induced alterations of DNA methylation in barley and their putative role in perturbed gene expression. Using Next Generation Sequencing, we screened the leaf and root methylomes of five divergent barley varieties grown under control and three salt concentrations, …

Deciphering Mechanisms Governing The Development Of The Rod Epigenome, Philip Andrew Ruzycki

Arts & Sciences Electronic Theses and Dissertations

Precisely coordinated expression of distinct sets of genes is essential for cellular development and function, especially in complex multicellular organisms. This regulation is achieved by the action of transcription factors (TF), proteins that bind specific genomic locations and alter the activity state and packaging of the DNA to promote or repress gene expression. However, while tremendous effort has defined networks of transcription factors that work together to drive specific phenotypes, little is known about their differential activity at the hundreds or thousands of sites where they bind. There are also many questions regarding the basic principles of the packaging of …

Characterizing Epigenetic Regulation In The Developing Chicken Retina, Bejan Abbas Rasoul

Masters Theses, 2010-2019

The retina, the sensory neuronal tissue within the eye, is composed of three layers of neuronal cells connected by two synaptic layers lining the inside of the anterior portion of the eye. Multipotent retinal precursor cells are genetically homogeneous and differentiate into mature retinal neurons due to differential gene expression. Differences in gene expression have been correlated with epigenetic modifications such as DNA methylation. DNA methylation of upstream regulatory elements is associated with transcriptional silencing of gene expression. Years of research in retinal development has identified the numerous genes expressed during the main steps of retinal development, however, it is …

Trim24 As An Oncogene In The Mammary Gland, Aundrietta Duncan

Dissertations & Theses (Open Access)

Despite the many advances made in breast cancer research and treatments, breast cancer remains one of the deadliest diseases plaguing women worldwide. While many findings on genetic mutations and their role in predisposing people to breast cancer have been uncovered, we are just beginning to understand the extent to which epigenetic regulators promote tumorigenic phenotypes, metastasis, and chemotherapeutic resistance. Moreover, new experimental tools offer the ability to address questions we were previously unable to assess. My project takes advantage of a new mouse model to understand the role of a proto-oncogenic, transcriptional co-regulator, TRIM24, in mammary gland development and disease. …

The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland

Dissertations & Theses (Open Access)

DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases. For example, cancer cells usually show global hypomethylation and regional hypermenthylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is …

Metabolic And Inflammatory Biomarkers Are Associated With Epigenetic Aging Acceleration Estimates In The Goldn Study, Marguerite R. Irvin, Stella Aslibekyan, Anh Do, Degui Zhi, Bertha Hidalgo, Steven A. Claas, Vinodh Srinivasasainagendra, Steve Horvath, Hemant K. Tiwari, Devin M. Absher, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background: Recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. However, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids.

Methods: We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5′-Cytosine-phosphate-guanine-3′ genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least …

Investigation Of Alcohol-Induced Changes In Hepatic Histone Modifications Using Mass Spectrometry Based Proteomics, Crystina Leah Kriss

USF Tampa Graduate Theses and Dissertations

Alcohol liver disease (ALD) is a major health concern throughout the world. Currently, in the United States, 17 million people suffer from alcoholism, of which 1.4 million people are receiving treatment [1, 2]. The link between ethanol metabolism, reactive oxygen species (ROS) and liver injury in ALD has been well characterized over the last couple decades [3-10]. Ethanol metabolism relies on the availability of the cofactor NAD+ for the oxidation of ethanol into acetate, consequently causing alterations in redox potential. Redox dysfunction within the mitochondria can affect multiple pathways important in maintaining cellular homeostasis. Chapter 1 provides an introduction to …

Impacts Of Genome And Nuclear Architecture On Molecular Evolution In Eukaryotes, Xyrus Maurer-Alcalá

Doctoral Dissertations

The traditional view of genomes suggests that they are static entities changing slowly in sequence and structure through time (e.g. evolving over geological time-scales). This outdated view has been challenged as our understanding of the dynamic nature of genomes has increased. Changes in DNA content (i.e. polyploidy) are common to specific life-cycle stages in a variety of eukaryotes, as are changes in genome content itself. These dramatic genomic changes include chromosomal deletions (i.e. paternal chromosome deletion in insects; Goday and Esteban 2001; Ross, et al. 2010), developmentally regulated genome rearrangements (e.g. the V(D)J system in adaptive immunity in mammals; Schatz …

Chromatin Organizer Ctcf In Brain Development And Behaviour, Adrienne Elbert

Electronic Thesis and Dissertation Repository

Chromatin architecture is an important regulator of gene expression, which dictates development. Mutations in one copy of the CTCF chromatin organizer gene cause intellectual disability and autism. Polymorphisms in CTCF have also been associated with increased risk for schizophrenia, a condition that overlaps in biological etiology with autism and intellectual disability. In this thesis, we sought to understand the role of CTCF in neurodevelopment using brain-specific conditional knockout and heterozygote mouse models. Using the Ctcf-null animals, we identify a cell-autonomous role for CTCF in regulating cortical interneuron development in the medial ganglionic eminence (MGE) through the transcriptional control of …

Characterizing The Requirement Of The Cmi/Trr Compass-Like Complex During Drosophila Development, Timothy Nickels

Master's Theses

The MLR family of COMPASS-like complexes are histone methyltransferase complexes that are associated with the activation of gene enhancers. In D. melanogaster, Cara mitad (Cmi, also known as Lpt) and Trithorax related (Trr) are central subunits of a complex orthologous to mammalian Lysine methyltransferase 2 C and D (KMT2C and KMT2D, also known as MLL3 and MLL2/4) that catalyze H3K4 monomethylation. Previous studies have demonstrated that mutations in these genes are associated with cancer and developmental disorders, but the mechanisms by which these alterations contribute to disease states are unknown. The Cmi-containing COMPASS-like complex and orthologous vertebrate complexes have been …

Maternal Engineered Nanomaterial Inhalation During Gestation Alters The Fetal Transcriptome, P.A. Stapleton, Q.A. Hathaway, C.E. Nichols, A.B. Abukabda, M.V. Pinti, D.L. Shepherd, C.R. Mcbride, J. Yi, V.C. Castranova, J.M Hollander, Timothy Robert Nurkiewicz

Faculty & Staff Scholarship

Background: The integration of engineered nanomaterials (ENM) is well-established and widespread in clinical, commercial, and domestic applications. Cardiovascular dysfunctions have been reported in adult populations after exposure to a variety of ENM. As the diversity of these exposures continues to increase, the fetal ramifications of maternal exposures have yet to be determined. We, and others, have explored the consequences of ENM inhalation during gestation and identified many cardiovascular and metabolic outcomes in the F1 generation. The purpose of these studies was to identify genetic alterations in the F1 generation of Sprague-Dawley rats that result from maternal ENM inhalation during gestation. …

Selective Inhibition Of Ctcf Binding By Ias Directs Tet-Mediated Reprogramming Of 5-Hydroxymethylation Patterns In Ias-Transformed Cells, Matthew Rea, Tyler Gripshover, Yvonne N. Fondufe-Mittendorf

Molecular and Cellular Biochemistry Faculty Publications

Methylation at cytosine (5mC) is a fundamental epigenetic DNA modification recently associated with iAs-mediated carcinogenesis. In contrast, the role of 5-hydroxymethylcytosine (5hmC), the oxidation product of 5mC in iAs-mediated carcinogenesis is unknown. Here we assess the hydroxymethylome in iAs-transformed cells, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks. Moreover, this pathologic iAs-mediated carcinogenesis is characterized by a shift toward a higher hydroxymethylation pattern genome-wide. At specific promoters, hydroxymethylation correlated with increased gene expression. Furthermore, this increase in hydroxymethylation occurs concurrently with an upregulation of ten-eleven translocation (TET) enzymes that oxidize 5-methylcytosine (5mC) in DNA. To …

The Effects Of Forest Degradation On Dna Methylation In Central African Songbirds, Andrew K. Wiegardt

Cal Poly Humboldt theses and projects

Environmentally-induced stress can initiate a molecular response through DNA methylation, which can alter gene expression, thereby serving as a mechanism allowing individuals to acclimate to a changing environment within their lifetime. In addition to DNA methylation, the production and release of corticosterone is a physiological mechanism by which birds can cope with acute environmental stressors. To assess how environmental stress impacted DNA methylation and corticosterone, I collected blood and feather samples from three understory avian species (Alethe castanea, Bleda notatus and Pseudalethe poliocephala), along a disturbance gradient in the lowland Guinean rainforest adjacent to the village of …