Life Sciences Commons^™

Connections Between Mechanosensitive Ion Channel Msl10 And Er-Plasma Membrane Contact Sites, Jennette Marie Codjoe

Arts & Sciences Electronic Theses and Dissertations

Mechanosensitive (MS) ion channels are an evolutionarily conserved way for cells to sense mechanical forces and transduce them into ionic signals. A plasma membrane-localized MS channel from Arabidopsis thaliana, MscS-Like (MSL)10, senses cell swelling and initiates a signaling cascade that triggers programmed cell death. Whereas the channel properties of MSL10 have been well studied, how MSL10 signals remains largely unknown. I worked collaboratively to show that important lesions for cell death signaling in the cytosolic N- and C-terminal domains of MSL10 interact genetically. I also helped show that ionic flux through MSL10 is dispensable for signaling, which suggested that MSL10 …

Understanding Gene Regulation With High-Throughput Genome-Integrated Reporter Assays, Clarice Hong

Arts & Sciences Electronic Theses and Dissertations

Proper spatiotemporal gene expression depends on specific interactions between cis-regulatory sequences (CRSs) and chromatin modifications at a genomic location. However, we do not yet understand the rules that determine how CRSs work together to influence gene expression. The goal of this thesis is to systematically assay and quantify how different genomic environments interact with CRSs to control gene expression output using a variety of genome-integrated massively parallel reporter assays (MPRAs). First, we tested the hypothesis that core promoters confer specificity by only responding to compatible enhancers and chromatin in specific genomic environments. We measured the activities of hundreds of core …

Bioinformatics And Cancer Genomics Approaches To Advance Precision Medicine And Elucidate Tumor Mutational Landscapes, Kelsy Cotto

Arts & Sciences Electronic Theses and Dissertations

Next-generation sequencing of DNA and RNA continues to be integrated into pre-clinical and clinical research. However, challenges still remain that impede the translation of findings into an improved understanding of human diseases or clinically actionable alterations. The projects described in this dissertation start with compiling efforts from experts who have identified druggable genes within the human genome, followed by in-depth analyses which characterize the pan-cancer landscape of splice-associated mutations and noncoding, regulatory mutations across multiple subtypes of breast cancer. In Chapters 2 and 3, substantial efforts were made to update the content and the user experience for the drug-gene interaction …

The Role Of The Neurodevelopmental Disorder Gene Myt1l In Mammalian Brain Development, Jiayang Chen

Arts & Sciences Electronic Theses and Dissertations

Recent human genetic studies have associated mutations in a gene called Myelin Transcription Factor 1 Like (MYT1L) with neurodevelopmental disorders (NDDs). Patients with MYT1L loss of function (LoF) mutations (MYT1L Syndrome patients) demonstrate shared symptoms such as microcephaly, attention deficit and hyperactivity disorder (ADHD), and obesity. Despite prior studies showing MYT1L overexpression facilitates neuronal differentiation in vitro, its functions in vivo, especially in the mammalian brain, and how its mutation leads to human disease pathology remains poorly understood. Here, I established the first mouse model of MYT1L Syndrome mimicking a patient specific LoF mutation. I found mice with Myt1l heterozygous …

Genetic And Transcriptomic Aspects Of Major Depressive Disorder: In Vivo Functional Assays Of Risk-Associated Variation, Candidate Disease Cell Types, And Their Pharmacologic And Sex Interactions, Bernard Mulvey

Arts & Sciences Electronic Theses and Dissertations

Major depressive disorder (MDD) is a debilitating illness that affects hundreds of millions globally, with substantial personal, medical, economic, and societal consequences. While depression occurs more commonly in females, the biology of the brain and sex underlying this skewed prevalence remains unclarified. This body of work explores two aspects of how biological sex may influence the brain at the level of gene expression: through intrinsic sex differences and through sex-mediated effects of depression risk genetics.

The monoamine hypothesis of depression suggests that modulatory neurotransmitters including serotonin and norepinephrine constitute a key axis in development of MDD. Large-scale studies of MDD …

Defining The Role Of Rare Genetic Variants That Drive Risk And Pathogenesis Of Alzheimer’S Disease, Matthew James Rosene

Arts & Sciences Electronic Theses and Dissertations

Alzheimer’s disease (AD) is the leading cause of dementia and is pathologically defined by the aggregation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Rare heritable mutations within the genes for amyloid precursor protein (APP) and presenilin 1 (PSEN1), and presenilin 2 (PSEN2) cause early onset AD and account for approximately 1% of AD cases. While the majority of AD cases are late-onset (LOAD), which is defined by a markedly more complex genetic architecture that is comprised of many genetic risk factors that influence AD through multiple cellular pathways. The advent of deep sequencing analyses have allowed for the identification …

Understanding The Role Of Involucrin In Skin Inflammation, Alina Schmidt

Arts & Sciences Electronic Theses and Dissertations

Terminally differentiated keratinocytes are essential for skin barrier function and are surrounded by an involucrin (IVL)-rich cornified envelope. Increased IVL expression in the epidermis is associated with recent positive selection in European populations, yet the functional significance of this finding is unclear. An upstream enhancer of IVL, the 923 enhancer, regulates IVL expression, and the impact of IVL enhancer variants on involucrin expression in modifying the penetrance of filaggrin (FLG) loss-of-function variants associated with atopic dermatitis (AD) has not been explored. I hypothesize involucrin to modulate the environmentally sensitive Vitamin D receptor (Vdr) activity in the epidermis and involucrin enhancer …