Open Access. Powered by Scholars. Published by Universities.®

Molecular Biology Commons

Open Access. Powered by Scholars. Published by Universities.®

Articles 1 - 11 of 11

Full-Text Articles in Molecular Biology

Linking Acetyl-Coa Metabolism And Histone Acetylation To Dynamic Gene Regulation In Yeast And Mouse Hippocampus, Philipp Mews Jan 2016

Linking Acetyl-Coa Metabolism And Histone Acetylation To Dynamic Gene Regulation In Yeast And Mouse Hippocampus, Philipp Mews

Publicly Accessible Penn Dissertations

A compelling body of evidence suggests an intimate relationship between metabolic state and chromatin regulation. This link is manifested in key metabolites that participate in biochemical pathways as intermediates, and function as cofactors to regulate chromatin modifying enzymes. Of particular interest is the metabolite acetyl-CoA, given its central role as an intermediate of cellular energy metabolism and key determinant of all histone acetylation. How nuclear acetyl-CoA levels are regulated to, in turn, control histone acetylation is under intense investigation, and holds promise for increased understanding of the molecular mechanisms adapting gene expression to internal and external stimuli. We studied the ...


Centromere Identity And The Nature Of The Cenp-A-Containing Nucleosome, Samantha Jane Falk Jan 2016

Centromere Identity And The Nature Of The Cenp-A-Containing Nucleosome, Samantha Jane Falk

Publicly Accessible Penn Dissertations

The centromere is an essential chromosomal locus that serves as the site of kinetochore formation, ensuring accurate chromosome segregation during mitosis and meiosis. While most centromeres form on repetitive DNA, the underlying DNA sequence is neither necessary nor sufficient to support centromere function, suggesting that this locus is epigenetically defined. The histone H3 variant centromere protein A (CENP-A) replaces H3 in nucleosomes at the centromere and is the best candidate to provide this epigenetic mark. This thesis aims to understand the features of the CENP-A nucleosome that impart its ability to mark and stabilize functional centromeres. In the first part ...


The Mitotic Genome: Accessibility And Transcriptional Control, Chris Hsiung Jan 2016

The Mitotic Genome: Accessibility And Transcriptional Control, Chris Hsiung

Publicly Accessible Penn Dissertations

Mitosis entails dramatic global alterations to genome structure and regulation, including

chromosome condensation, dissociation of the transcriptional machinery from chromosomes, and transcriptional silencing. Here I report studies that address the macromolecular accessibility of the mitotic genome and the control of transcriptional reactivation upon mitotic exit in a mammalian cell line. The results obtained from measuring the sensitivity of chromatin to DNase I cleavage by sequencing (DNase-seq) in pure mitotic cell populations demonstrate that macromolecular accessibility of the mitotic genome is widely preserved. Thus, steric hindrance from chromatin condensation is insufficient for explaining the eviction of transcription factors from mitotic chromatin ...


Dna Disentangled: Roles For Sgs1 And Top3 In Rec-X Resolution And Replication Fork Restart, Mary Rebecca Glineburg Jan 2016

Dna Disentangled: Roles For Sgs1 And Top3 In Rec-X Resolution And Replication Fork Restart, Mary Rebecca Glineburg

Publicly Accessible Penn Dissertations

Homologous recombination (HR), becomes important for repair during replication where completion of DNA synthesis relies on recombination intermediate-mediated lesion bypass. For decades, Holliday Junctions (HJs) were considered the primary recombination intermediate utilized during this repair process, but increasing evidence points out two strong discrepancies: 1) X-structures, when present, are often biochemically inconsistent with being HJs, and 2) despite HR mutants being sensitive to numerous DNA damaging agents, most insults don’t result in X-structure accumulation, suggesting alternative HR pathways are at play. The Sgs1-Top3-Rmi1 (STR) complex, in Saccharomyces cerevisiae, is vital for maintaining genome integrity, and is known to resolve ...


Mining Genomic Variants And Causal Pathways Linking Hdl And Triglycerides To Coronary Disease, Sumeet Anand Khetarpal Jan 2016

Mining Genomic Variants And Causal Pathways Linking Hdl And Triglycerides To Coronary Disease, Sumeet Anand Khetarpal

Publicly Accessible Penn Dissertations

Blood lipids are important biomarkers of risk of coronary heart disease (CHD), the leading cause of death in the world. Myriad data support a causal role of low-density lipoprotein cholesterol (LDL-C) in increasing risk of CHD. Long-standing epidemiology suggests that high-density lipoprotein cholesterol (HDL-C) may protect from disease while high triglycerides (TGs) increase CHD risk. However, the causality of HDL-C and TG to CHD remains controversial. New genetic methodologies have allowed a better look into causal pathways underlying relationships between these traits and disease. Using a combination of approaches for interrogating rare genetic variation in humans, we investigated how HDL ...


Genetic Requirement For The Rna Helicase Mov10l1 In Pirna Biogenesis, Qi Fu Jan 2016

Genetic Requirement For The Rna Helicase Mov10l1 In Pirna Biogenesis, Qi Fu

Publicly Accessible Penn Dissertations

GENETIC REQUIREMENT FOR THE RNA HELICASE MOV10L1 IN PIRNA BIOGENESIS

Qi Fu

P. Jeremy Wang

Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs required for transposon silencing, germ cell development, and fertility in many eukaryotic species. However, many of the mechanisms underlying piRNA biogenesis have not been elucidated. Studies of MOV10L1 support its function as an RNA helicase in the processing of piRNA precursors. In this study, we elucidate the requirement for MOV10L1 RNA helicase activity in piRNA biogenesis.

To determine the requirement for MOV10L1 RNA helicase activity in piRNA biogenesis in vivo, we generated two knock-in mouse ...


Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives, David Tischfield Jan 2016

Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives, David Tischfield

Publicly Accessible Penn Dissertations

The embryonic subpallium produces many different neuronal cell types present throughout the adult telencephalon, including striatal medium spiny neurons (MSN) and cortical interneurons. Dysfunction of either cell type leads to neurological and psychiatric disorders including schizophrenia, epilepsy, and Tourette’s syndrome. Thus, understanding the molecular pathways that regulate their development and function has important implications for understanding disease pathogenesis. This work describes novel methods and genetic factors that expand our ability to characterize the development and function of two major subpallial derivatives: cortical interneurons and striatal MSN. The first part of this thesis characterizes a novel enrichment method for producing ...


Insights Into Terminal Erythropoiesis Influenced By Human Genetic Variation, Elizabeth Traxler Jan 2016

Insights Into Terminal Erythropoiesis Influenced By Human Genetic Variation, Elizabeth Traxler

Publicly Accessible Penn Dissertations

Red blood cells (RBCs) carry hemoglobin, enabling delivery of oxygen to all tissues of the body. They are the products of a highly specialized differentiation process that begins with a hematopoietic stem cell and results in an enucleated, biconcave RBC. This thesis is focused on the use of human genetic studies to gain a better understanding of the molecular processes occurring during terminal erythroid differentiation. We studied the regulation and roles of two erythroid-restricted genes, Trim58 and Hemoglobin Gamma Chain (HBG1 and HBG2, γ-globin), by using a combination of loss-of-function techniques, including RNA-interference-mediated gene suppression, a mutant mouse model, and ...


Epigenetic Regulation Of The Dlk1-Meg3 Imprinted Locus In Human Islets, Vasumathi Kameswaran Jan 2016

Epigenetic Regulation Of The Dlk1-Meg3 Imprinted Locus In Human Islets, Vasumathi Kameswaran

Publicly Accessible Penn Dissertations

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by inadequate insulin secretion by the pancreatic β-cell in response to increased blood glucose levels. Despite compelling evidence that T2DM has a high rate of familial aggregation, known genetic risk variants account for less than 10% of the observed heritability. Consequently, post-transcriptional regulators of gene expression, including microRNAs and other noncoding RNAs, have been implicated in the etiology of T2DM, in part due to their ability to simultaneously regulate the expression of hundreds of targets.

To determine if microRNAs are involved in the pathogenesis of human T2DM, I sequenced ...


Contextual Insights Into The Rett Syndrome Transcriptome, Brian Scott Roosevelt Johnson Jan 2016

Contextual Insights Into The Rett Syndrome Transcriptome, Brian Scott Roosevelt Johnson

Publicly Accessible Penn Dissertations

Mutations in MECP2 are responsible for Rett syndrome (RTT), a severe X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and motor impairments. However, molecular insight into how these mutations affect the neuronal transcriptiome, disrupt neuronal function and contribute to RTT is impeded by the cellular heterogeneity of the mammalian brain. A comparison between gene expression changes in the striatum, hypothalamus, and cerebellum of MeCP2-null mice revealed that gene expression changes are distinct between different brain regions, which suggests that MeCP2 function should be understood in a cell type-dependent context. To accomplish this task, I generated and phenotypically ...


Potentiated Hsp104 Variants Suppress The Toxicity Of Most Overexpressed Dosage-Sensitive Yeast Genes, Michael Yancey Soo Jan 2016

Potentiated Hsp104 Variants Suppress The Toxicity Of Most Overexpressed Dosage-Sensitive Yeast Genes, Michael Yancey Soo

Publicly Accessible Penn Dissertations

Maintenance of optimal gene expression levels is critical for cell viability and homeostasis. However, misregulation of gene expression can and regularly occur. One type of detrimental misregulation involves overexpression of a single gene that can cause organismal death is dosage sensitivity, which is often due to increased concentration of the protein encoded by the gene. Deleterious increases in the expression of specific proteins are associated with various neurodegenerative diseases such as Parkinson’s and Alzheimer’s Diseases as well as other cellular maladies including various cancers and Down Syndrome. In yeast, it has been estimated that ~20% of genes are ...