Biological Sciences

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Analyzing the In Vivo Roles of Histone Acetyltransferases GCN5 And ESA1 in RSC Recruitment and Remodeling Activity Genome-Wide in Saccharomyces Cerevisiae
(2023-01-01) Biernat, Emily R.; Govind, Chhabi K; Chaudhry, Rasul; Blumer-Schuette, Sara
Transcription is important for gene expression and is a tightly-controlled process involving multiple mechanisms of regulation, including regulation by chromatin structure. Chromatin consists of nucleosomes, which are comprised of DNA wrapped around histone proteins. Chromatin remodelers such as the Remodels the Structure of Chromatin (RSC) complex play important roles in controlling DNA accessibility to the transcriptional machinery and organizing chromatin throughout the genome. Mutations in yeast and mammalian RSC orthologs have been linked to dysregulated cell cycle progression, chromosome segregation, stress response, and developmental processes. In this study, we investigated the mechanisms by which RSC associates with chromatin on a genome-wide scale and the impact of disrupted RSC-chromatin interactions on transcription. Previous studies have suggested that nucleosome acetylation via histone acetyltransferases (HATs) may facilitate RSC binding to chromatin. To explore this, we examined the effects of removing HATs Gcn5 and Esa1 on RSC occupancy. Surprisingly, our results revealed distinct effects of HAT loss on RSC occupancy at promoters and gene bodies. In promoters, the loss of HATs increased RSC association with promoter nucleosomes, particularly in promoters containing partially-unwrapped fragile nucleosomes. Additionally, we found that HAT-mediated acetylation is crucial for maintaining nucleosome depletion at promoters. Conversely, HAT loss decreased RSC occupancy in gene bodies of highly transcribed genes. This reduction in RSC binding was dependent on histone tails, as cells lacking these tails also showed a significant loss of RSC binding to gene bodies. High-resolution mapping and analyses demonstrated that RSC-bound nucleosomes, particularly in gene bodies, were highly accessible. Consistent with these findings, loss of HAT functions resulted in widespread transcriptional changes, impacting both transcription initiation and elongation. This work provides valuable insights into how HAT-mediated histone modifications regulate RSC association with chromatin and the consequent impact on global transcription.
Assessment of Taxon Sampling on Phylogenetic Reconstructions and Timetrees: A New Methodology And Application
(2023-01-01) Powell, Christopher Lowell Edward; Battistuzzi, Fabia Ursula; Oleksyk, Taras K; Blumer-Schuette, Sara E
Over the past three decades, computational capabilities have grown at such a rapid rate that they have given rise to many computationally heavy science fields such as phylogenomics. As increasingly more genomes are sequenced in the three domains of life, larger and more species-complete phylogenetic tree reconstructions are leading to a better understanding of the Tree of Life and the evolutionary histories in deep times. However, these large datasets pose unique challenges from a modeling and computational perspective: accurately describing the evolutionary process of thousands of species is still beyond the capability of current evolutionary models while the computational burden limits our ability to exhaustively explore and test multiple hypotheses. These limitations become even more problematic when attempting to estimate the absolute times within these phylogenetic reconstructions (timetrees). These time estimations are not only constrained computationally by run times and resource requirements but also bound by the availability of fossil data to estimate divergence times for the evolution of species (primary calibrations). All of these issues are particularly severe in prokaryotes, because of the high number of species available in databases, their large evolutionary variability, and the few primary calibrations available. Yet, they represent two out of the three domains of life and are therefore key to reconstructing the Tree of Life. This combination of computational and data constraints is forcing researchers to make choices on the datasets being analyzed without a clear understanding of the consequences of these choices on the accuracy of the results obtained. This work presents an in-depth analysis of the effects of dataset choices on the reconstruction of phylogenetic histories using a newly developed tool (Phylogenetic Assessment of Taxon Sampling) that will enable fast, simple, and reproducible testing of taxon sampling. The PATS pipeline is available on GitHub: https://github.com/BlabOaklandU/PATS
Leveraging Big Data for Bioinformatic Analysis in Modern Population Genomics
(2023-01-01) Wolfsberger, Walter; Oleksyk, Taras K; Battistuzzi, Fabia; Westrick, Randal
The technological advancements and the cost reduction of genomic sequencing provide novel capabilities to pose and answer biological questions on a grand scale. The initial efforts of establishing genomic references for many species of the globe serve as a foundation for the projects that aim to analyze the populations of said species. This expansion of the number of samples involved in individual studies is often connected with increased infrastructural costs for data storage and analysis. Population genomics methods are expanding on the existing genetic approaches, leveraging our ability to automate big data processing and introducing comparative methods to our collection of scientific instruments. It has extensive applications in animal and wildlife research, conservation, and human population analyses. These unique opportunities are associated with emerging challenges related to the nature of the approaches and their relative novelty in the field. Analysis of a multitude of individuals often increases requirements in terms of bioinformatics expertise and resources. An increase in complexity and data volume means researchers often need access to high-performance computing facilities and specific training to utilize them. The field still grows, with new instruments or tests frequently introduced and outdated approaches depreciating. This work reviews population genomics methods and their application related to wildlife research, conservation, and human populations research, employs them to provide answers in multiple studies, and presents a newly developed analysis suite. The suite is aimed to facilitate reproducible, accessible population genomic testing across various fields of application, seeking to address the growing expertise challenges in the field.
Medically Relevant Genome Diversity in Ukraine
(2023-01-01) Shchubelka, Khrystyna; Oleksyk, Taras K; Battistuzzi, Fabia; Raffel, Thomas
Ukraine, the second-largest country in Europe, has a rich history characterized by migrations, epidemics, famines, wars, and occupations, all of which have contributed to the formation of the modern Ukrainian population. However, the genetic composition of Ukraine remains understudied. Previous population genetic studies have largely overlooked the unique genetic makeup of Ukraine due to lack of publicly available genomic data. Yet, recent global assessments of genome diversity have highlighted the presence of numerous endemic variants, underscoring the significance of investigating genetic variation in underrepresented regions like Eastern Europe and, specifically, Ukraine. Such research is vital in the context of worldwide clinical trials and the development of personalized medicine. Local populations, shaped by their distinct histories, harbor a wealth of unexplored genomic variation, which may impact drug response, influence the risk of common and rare diseases, and shape lifestyle adaptations.Comprehensively understanding the genetic makeup of specific populations facilitates more effective identification of genetic markers for disease gene mapping, including family linkage and genome-wide association studies. These investigations aim to uncover susceptibility genes or loci for both Mendelian and complex diseases. Therefore, in this discovery-based study, our objective is to characterize the extensive genetic variation of medically relevant alleles in contemporary Ukraine across various levels of population structure: within major regions of Ukraine, and among the multiethnic population of Transcarpathia. Additionally, we will explore the relationship between lactose persistence genotypes and phenotypes, as well as the genetic factors underlying global developmental delay and intellectual disability in Ukraine.
Studying the Role of PTEN in The Gut and Investigating the Gut-Brain Inflammatory Interaction
(2023-01-01) Howe, Cody Scott; Rhee, Sang H; Madlambayan, Gerard; Song, Mi Hye
Phosphatase and tensin homolog (Pten) deficiency causes tumorigenesis because Pten opposes PI3k-Akt signaling. However, correlation between Pten deficiency and colon cancer remains unclear due to contradicting studies. The first project examines this correlation by generating intestinal epithelial cell (IEC) – specific Pten knockout (KO) mice. However, IEC-Pten deficiency alone did not induce tumorigenesis in mice but maintained the tumor-driving potential. The expression of tumor-promoting and tumor-suppressing genes was decreased and increased, respectively, in the intestine of PtenΔIEC/ΔIEC mice compared to controls. The abundance of Akkermansia muciniphila, capable of inducing chronic intestinal inflammation, was reduced in PtenΔIEC/ΔIEC mice. These findings suggest that altered tumor-associated gene expression and changed gut microbiota shape a tumor-preventive microenvironment in PtenΔIEC/ΔIEC mice. It was recently suggested that PTEN regulates TLR5-induced immune and inflammatory responses in IECs, suggesting an immunomodulatory function of PTEN in the gut. However, this alternative function of PTEN has not been evaluated in an in vivo context of protection against enteropathogenic bacteria. In the second project, PtenΔIEC/ΔIEC mice were subjected to the streptomycin-pre-treated mouse model of Salmonella infection. The bacterial infection in PtenΔIEC/ΔIEC mice increased the mortality, induced gastrointestinal inflammation, up-regulated pro-inflammatory cytokines, and increased bacterial loads in extraintestinal tissues. This suggests that IEC-restricted Pten deficiency renders the host greatly susceptible to Salmonella infection and supports an immune-regulatory role of PTEN in the gut. Lastly, in the third project, chronic gut inflammation is associated with neurodegenerative diseases. However, the direct evidence for and the underlying mechanism of the gut-brain interaction remain obscure. An interleukin-10 (IL-10) KO mouse was fed piroxicam-mixed chow, where it found that the brain and gut had increased levels of IL-1β and IL-6 cytokines. These findings suggest an inflammatory link in the piroxicam-fed IL-10 KO mice. Pten is an important factor in maintaining gut homeostasis, which is important for neural function.
The New Zealand Mud Snail (Potamopyrgus Antipodarum) Ecology And Management Of A Global Invader
(2022-07-28) Gist, Jeremy A.; Tiegs, Scott; Berven, Keith; Luttenton, Mark; Strayer, David
The New Zealand mud snail (Potamopyrgus antipodarum; NZMS) is among the most globally widespread aquatic invaders, colonizing at least 40 countries across 6 continents. NZMS have recently colonized rivers of the Laurentian Great Lakes region. where little is known about their impacts on the native communities of the ecosystems they invade. In chapter one, I present the results of a systematic review of 245 articles, and outline NZMS impacts, distribution, population dynamics, vectors of spread, and management. The invasion success of NZMS stems from their opportunistic traits allowing them to tolerate broad ranges of environmental conditions. However, optimal conditions for successful establishment are evident. NZMS can become exceptionally abundant and impact multiple facets of aquatic ecosystems, though populations can fluctuate seasonally and over longer time scales, likely due to environmental constraints. In chapter two, I tested the efficacy of three different chemical reagents for NZMS decontamination on recreational fishing gear and combined these results with results of a self-administered public survey gauging the level of willingness individuals have to participate in a given NZMS decontamination technique. The greatest mortality of NZMS was caused by Formula 409, and participants of the survey revealed Formula 409 to be the chemical they'd be most willing to use. Chapter three outlines an investigation of the effects of NZMS on the diets and condition of fish in a recently invaded stream, the Au Sable River (Michigan, USA). Trout consumed NZMS throughout the duration of the study, while sculpin minimally consumed NZMS. Of the 83 trout collected, 60% contained NZMS in their stomachs. Age 2 trout that consumed NZMS exhibited reduced condition relative to those that contained fewer NZMS. Lastly, chapter four consists of a study to characterize NZMS population dynamics and their effects on native benthic invertebrates in the Au Sable River. NZMS populations exhibited pronounced seasonality with peak densities typically occurring during the Summer and Autumn of each year. NZMS numerically dominated the benthic community and were associated with differences in the overall benthic community composition. The results of these studies highlight how NZMS can affect native communities and higher consumers in rivers of the Great Lakes region and contribute to a more robust understanding of the global NZMS invasion, such that undesired impacts can be minimized or averted.
Thermal Biology of Parasites and Their Hosts in the Laboratory and Classroom
(2024-01-01) Craig, Hunter Michael; Raffel, Thomas R.; Berven, Keith A.; Moore, Shaun A.
The threat of climate change makes it increasingly important for biologists and the public to understand how organisms respond to temperature. The Metabolic Theory of Ecology (MTE) predicts that temperature should affect organism performance, with implications for species interactions and ecosystems that span disciplines including mathematics, chemistry, and biology. Temperature strongly impacts parasitic diseases of ectothermic hosts, with important implications for diseases of humans and wildlife. It is thus vital to examine metabolic responses of hosts and parasites to temperature in research laboratories and classroom education. I used MTE-based models to describe thermal responses of the pathogen Batrachochytrium dendrobatidis (Bd) and its amphibian hosts (Notophthalmus viridescens, eastern red-spotted newts). I measured newt breath rate and oxygen consumption (Chapter 2), as well as Bd zoospore swimming speed and critical thermal maximum (Chapter 3), to parameterize MTE-based models of host and parasite thermal performance. I conducted a controlled-temperature Bd infection experiment with newts collected from different latitudes (Chapter 4). In all three experiments, I also used temperature shifts to test for thermal acclimation effects. I hypothesized that newts and Bd would exhibit beneficial acclimation, but that Bd would acclimate to a new temperature faster because of its smaller mass and faster metabolism. I found little evidence of thermal acclimation effects on host performance, but my results suggested that the Bd either shows no acclimation or very rapid (< 3 minutes) acclimation responses. I also combined scholarship of research with scholarship of learning by developing an online teaching lab activity that introduces students to MTE-based thermal models by contrasting thermal responses in humans versus frogs (Chapter 5). I conducted a controlled experiment to compare learning outcomes for the online versus the face-to-face version of the activity (Chapter 6). Results varied, but students generally achieved similar learning outcomes in both versions of this activity.
Traumatic Brain Injury: Assessing The Pathogenic Impact Of Chronic Smoking And Potential Countermeasures
(2022-11-04) Sivandzade, Farzane; Cucullo, Luca; Al-Shabrawey, Mohamed; Liu Zijuan
Traumatic brain injury is among the most prevalent causes of cerebrovascular and neurological damage worldwide. Premorbid conditions such as smoking could exacerbate post-traumatic brain injury damage and impact recovery due to vascular endothelial dysfunction. Cigarette smoke produces reactive oxygen species (ROS) and oxidative stress (OS), driving endothelial dysfunction and damaging the blood-brain barrier (BBB) endothelium. Interestingly, these pathogenic modulators of BBB impairment are similar to those initiated by hyperglycemia. Thus, this work investigated the pathophysiological mechanisms underlying traumatic brain injury (TBI) exacerbation following chronic smoking and vaping exposure to determine key pathological parameters leading to loss of BBB function and integrity. I also assessed the effectiveness of metformin and rosiglitazone to prevent/reduce the loss of BBB function and integrity and protect the brain from the exacerbation of post-TBI likely promoted by the chronic exposure to tobacco smoke (TS) or electronic cigarette (EC) vape and unravel the corresponding mechanism (s) of action. For this purpose, I used both in vitro (primary brain microvascular endothelial cells) and in vivo mice models (male and C57BL/6J mice) subjected to TS/EC and TBI, with/without antidiabetic treatments. The outcomes of these studies would define the complex interplay between smoking and TBI and lead to new approaches for alleviating TBI outcomes.

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