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Full-Text Articles in Molecular Biology

Epigenetic Mechanisms Governing Behavioral Reprogramming In The Ant Camponotus Floridanus, Riley John Graham Jan 2018

Epigenetic Mechanisms Governing Behavioral Reprogramming In The Ant Camponotus Floridanus, Riley John Graham

Publicly Accessible Penn Dissertations

Eusocial insect colonies divide behaviors among specialist groups called castes. In some species, caste identity is determined by the interaction of endogenous (e.g. genomic) and exogenous (e.g. juvenile hormone from nurses) signals during larval development, suggesting epigenetic mechanisms underlie plastic traits tied to caste identity. Previous work demonstrated a link between patterns of histone H3 lysine 27 acetylation (H3K27ac) and caste-specific gene expression in Major and Minor workers of the ant Camponotus floridanus, and we hypothesized caste-specific behaviors such as foraging may be similarly regulated by histone acetylation. To test this hypothesis, we fed mature (~30d old) Majors ...


Reprogramming The Retina: Next Generation Strategies Of Retinal Neuroprotection And Gene Therapy Vector Potency Assessment, Devin Scott Mcdougald Jan 2018

Reprogramming The Retina: Next Generation Strategies Of Retinal Neuroprotection And Gene Therapy Vector Potency Assessment, Devin Scott Mcdougald

Publicly Accessible Penn Dissertations

Mutations within over 250 known genes are associated with inherited retinal degeneration. Clinical success following gene replacement therapy for Leber’s congenital amaurosis type 2 establishes a platform for the development of downstream treatments targeting other forms of inherited and acquired ocular disease. Unfortunately, several challenges relevant to complex disease pathology and limitations of current gene transfer technologies impede the development of gene replacement for each specific form of retinal degeneration. Here we describe gene augmentation strategies mediated by recombinant AAV vectors that impede retinal degeneration in pre-clinical models of acquired and inherited vision loss. We demonstrate distinct neuroprotective effects ...


Chromatin Remodeling Dynamics During Brown Adipogenesis, Suzanne Natalie Shapira Jan 2018

Chromatin Remodeling Dynamics During Brown Adipogenesis, Suzanne Natalie Shapira

Publicly Accessible Penn Dissertations

Brown adipose tissue (BAT) is specialized to expend energy through the action of the mitochondrial uncoupling protein UCP1. Increasing brown fat mass or activity through genetic or chemical manipulation in mice suppresses obesity and its comorbidities; as such, there is great interest in developing approaches to increase the amount and/or function of brown fat to combat metabolic disorders. My thesis work aimed to dissect the molecular mechanisms by which the helix- loop-helix transcription factor Early B-Cell Factor 2 (EBF2) regulates brown adipocyte commitment and terminal differentiation. Through analysis of tissue-specific knockout mouse models, we found that EBF2 is required ...


Β Cell Replacement Therapy: A Novel Application For Targeted Epigenetic Editing, Kristy Ou Jan 2018

Β Cell Replacement Therapy: A Novel Application For Targeted Epigenetic Editing, Kristy Ou

Publicly Accessible Penn Dissertations

Pancreatic β cells are the exclusive source of insulin, which normalizes blood glucose levels under hyperglycemic conditions. In 2015, over 252,000 deaths in the United States were contributed by diabetes, a family of disorders directly linked to defects in the pancreatic β cells. β cell deficiency or dysfunction leads to insufficient insulin secretion, resulting in chronic hyperglycemia and increased risk for severe health complications. Although severely diabetic patients can clinically manage their glucose levels with mealtime delivery of insulin analogues, many still experience potentially life-threatening hypoglycemic episodes due to erroneous insulin administration. Only β cell replacement therapy, through the ...


Dissecting The Functions Of Atr In Replication Fork Stability, Theonie Anastassiadis Jan 2017

Dissecting The Functions Of Atr In Replication Fork Stability, Theonie Anastassiadis

Publicly Accessible Penn Dissertations

Genome maintenance is required for cellular viability, and failure to preserve genomic integrity is associated with an increased risk of diseases, such as cancer. To ensure genomic stability, cells have checkpoints that control cell cycle progression in the event of DNA damage or incomplete DNA replication. The DNA replication checkpoint is regulated by the ATR-CHK1 pathway that stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Two distinct models have been proposed to explain how ATR stabilizes stalled forks: 1) through local modulation of fork remodelers, such as SMARCAL1 inhibition, and 2) through inhibition of CDK-dependent ...


Novel Cell Surface Anchoring Mechanism Of Prokaryotic Secreted Protein, Mohd Farid Abdul Halim Jan 2017

Novel Cell Surface Anchoring Mechanism Of Prokaryotic Secreted Protein, Mohd Farid Abdul Halim

Publicly Accessible Penn Dissertations

The microbial cell surface is decorated with a variety of protein structures that play important roles in key cellular processes such as providing cell stability, facilitating interactions between cells, and interacting with the environment. One important feature of the biosynthesis of these structures is the proper anchoring of proteins to the cell surface. In silico work recently predicted a novel protein anchoring mechanism for a subset of surface proteins that contain a conserved C-terminal tripartite architecture, which consists of a conserved motif, followed by a hydrophobic (H) domain, and positively charged amino acids. Using the well-studied model archaeon Haloferax volcanii ...


The Human Heterochromatin Landscape: Genomic Subtypes, Bound Proteins, And Contributions To Cell Identity, Justin S. Becker Jan 2017

The Human Heterochromatin Landscape: Genomic Subtypes, Bound Proteins, And Contributions To Cell Identity, Justin S. Becker

Publicly Accessible Penn Dissertations

Large portions of mammalian genomes are packaged into structurally compact heterochromatin, which protects genome integrity and suppresses transcription of lineage-inappropriate genes. Characterization of heterochromatic regions has relied on genomic mapping of associated histone modifications, such as H3K9me3 and H3K27me3, and purification of proteins interacting with these modifications. Heterochromatic regions marked by H3K9me3 have been shown to impede gene activation during reprogramming to pluripotency, and I find that H3K9me3 domains can similarly impede conversion of fibroblasts to hepatocytes. However, both H3K9me3 and H3K27me3 can be found in transcriptionally active chromatin, limiting the accuracy of histone marks alone for identifying heterochromatin domains ...


Transcriptome-Wide Analysis Of Hypoxic Cancer Cells Identify Alternative Splicing As A Mechanism To Inhibit Translation, Lauren Kathleen Brady Jan 2017

Transcriptome-Wide Analysis Of Hypoxic Cancer Cells Identify Alternative Splicing As A Mechanism To Inhibit Translation, Lauren Kathleen Brady

Publicly Accessible Penn Dissertations

Cellular adaptation to hypoxia involves downregulation of energy-consuming processes such as macromolecular synthesis, and leads to tumor aggressiveness and resistance to therapies for many solid cancers. To delineate mechanisms underlying this process, I carried out a transcriptome-wide study to measure hypoxia-mediated changes in gene expression and alternative splicing in in vivo and in vitro models of hypoxic head and neck carcinoma (HNC) cells. These data represent the first nucleotide-resolution study of the hypoxic transcriptome of HNC cells in vivo and in vitro. This investigation uncovered a global downregulation of genes known to regulate RNA processing, including a significant number of ...


Modulation Of Transcription In The Murine Gut Epithelium In Development, Differentiation, And Disease, Julia Elise Kieckhaefer Jan 2017

Modulation Of Transcription In The Murine Gut Epithelium In Development, Differentiation, And Disease, Julia Elise Kieckhaefer

Publicly Accessible Penn Dissertations

The intestinal epithelium is a continuously self-renewing tissue that must balance its function as the site of nutrient absorption with its role as a barrier between the body and the external environment. With its high cellular turnover and continual exposure to lumenal antigens, the intestinal epithelium is highly susceptible to developing diseases, such as inflammatory bowel disease (IBD) and cancer. Understanding the factors that control intestinal epithelial development are key to discovering disease etiology and to engineering new treatments. In mammals, studies have pointed to dysregulation of RNA Polymerase III as playing a role in oncogenic transformation. A deletion in ...


Genomics-Based Studies Identify Cis And Trans Acting Post-Transcriptional Regulators, Shawn W. Foley Jan 2017

Genomics-Based Studies Identify Cis And Trans Acting Post-Transcriptional Regulators, Shawn W. Foley

Publicly Accessible Penn Dissertations

The identity of every organism is stored in its genetic material. Each gene is transcribed into an intermediate RNA molecule, which undergoes complex processing before translation into a functional protein. RNA processing is controlled by RNA binding proteins (RBPs). Each RBP binds to and regulates the processing, stability, and translation of hundreds to thousands of RNA targets, thereby making these proteins essential for organismal development. RBPs bind to their targets by recognizing both the RNA sequence and secondary structure, which is the interaction between complementary RNA sequences within a single molecule. These interactions can be regulated by changing the chemical ...


The Cellular And Molecular Underpinnings Of Intestinal Epithelial Regeneration, Maryam Yousefi Jan 2017

The Cellular And Molecular Underpinnings Of Intestinal Epithelial Regeneration, Maryam Yousefi

Publicly Accessible Penn Dissertations

Injury to the intestinal epithelium is a hallmark of numerous common clinical disorders, including radiation enteropathy, ischemia-reperfusion, and inflammatory bowel diseases. Disruption of the epithelial barrier in these conditions must be quickly restored to avoid dehydration and translocation of gut microbiota to the bloodstream. Short-term calorie restriction can enhance regenerative response of the intestinal epithelium following DNA damaging injury. However, the specific cell type responsible for this enhanced regenerative capacity and as a result the molecular determinants of this process remain unknown.

Regeneration of the intestinal epithelium is driven by multiple intestinal stem cell (ISC) types, including an active, radiosensitive ...


Histone Deacetylase 3 And The Epigenomic Regulation Of Brown Adipose Physiology, Matthew Joseph Emmett Jan 2017

Histone Deacetylase 3 And The Epigenomic Regulation Of Brown Adipose Physiology, Matthew Joseph Emmett

Publicly Accessible Penn Dissertations

Brown adipose tissue (BAT) is a thermogenic organ, which helps to protect body temperature against cold and can counteract metabolic disease. Numerous pathways modulate the activity of BAT in a highly regulated and coordinated manner to exert tight control over its immense calorie burning capacity. However, less is known regarding the transcriptional and epigenomic mechanisms controlling the thermogenic gene program of brown adipocytes. Here, we show that histone deacetylase 3 (HDAC3) is required for the activation of BAT enhancers to ensure thermogenic aptitude, thus enabling survival of dangerously cold environmental temperature. Loss of HDAC3 leads to deficient expression of uncoupling ...


Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration, Michael Gallagher Jan 2017

Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration, Michael Gallagher

Publicly Accessible Penn Dissertations

Neurodegenerative diseases are an emerging global health crisis, with the projected global cost of dementia alone expected to exceed $1 trillion, or >1% of world GDP, by 2018. However, there are no disease-modifying treatments for the major neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis. Therefore, there is an urgent need for a better understanding of the pathophysiology underlying these diseases. While genome-wide association studies (GWAS) have identified ~200 genetic variants that are associated with risk of developing neurodegenerative disease, the biological mechanisms underlying these associations are largely unknown. This ...


Exposure To Heavy Metal Stress Regulates Intercellular Signaling Via Callose Deposition And Breakdown, Ruthsabel O'Lexy Jan 2017

Exposure To Heavy Metal Stress Regulates Intercellular Signaling Via Callose Deposition And Breakdown, Ruthsabel O'Lexy

Publicly Accessible Penn Dissertations

How organisms sense external cues and integrate them into developmental changes remains a large biological question. Plants, which are sessile organisms, are particularly vulnerable to challenges in their environment. An early response to abiotic and biotic stress in plants is the modification of intercellular signaling through plasmodesmata, cytoplasmic channels that connect adjacent cells. However, the different ways in which plasmodesmata-mediated signaling can be affected, the molecular players involved in this response, the genetic basis of this regulation, and the biological benefits of this response are still poorly understood.

Here, we take a survey of seven different agriculturally relevant stresses of ...


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 ...


Molecular Characterization Of The Transmission And Early Diversification Of Hepatitis C Virus, Mark Bevan Stoddard Jan 2015

Molecular Characterization Of The Transmission And Early Diversification Of Hepatitis C Virus, Mark Bevan Stoddard

Publicly Accessible Penn Dissertations

Hepatitis C virus (HCV) is a medically important RNA virus in the Flaviviridae family. It persists in chronically infected individuals by replicating in hepatocytes and by evolving as a genetically diverse "quasispecies" that evades host immune pressures. However, transmission, with its attendant population bottlenecking, represents a period of relative vulnerability and is of particular importance with respect to viral natural history, immunopathogenesis, treatment intervention, and vaccine development. A precise molecular characterization of HCV transmission and early diversification has not previously been possible. In this dissertation work, it was hypothesized that HCV genomes that are transmitted from one individual to the ...


Intrathecal Adeno-Associated Virus Vector Delivery For Mucopolysaccharidosis Type I, Christian Hinderer Jan 2015

Intrathecal Adeno-Associated Virus Vector Delivery For Mucopolysaccharidosis Type I, Christian Hinderer

Publicly Accessible Penn Dissertations

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from deficiency of the enzyme α-L-iduronidase (IDUA). Accumulation of the IDUA substrates heparan and dermatan sulfate causes widespread organ pathology. While many of the somatic manifestations of MPS I can be treated with intravenous enzyme replacement, the devastating CNS sequelae—cognitive impairment, spinal cord compression, and hydrocephalus—do not respond to treatment. Partial preservation of cognitive function is possible with early hematopoietic stem cell transplantation, although transplant is associated with substantial morbidity and mortality. Gene transfer using adeno-associated virus (AAV) vectors offers a potential alternative approach to deliver the ...


Dnmt1 In Intestinal Development And Cancer, Ellen Nichole Elliott Jan 2015

Dnmt1 In Intestinal Development And Cancer, Ellen Nichole Elliott

Publicly Accessible Penn Dissertations

Patterns of DNA methylation are established and maintained by DNA methyltransferases (Dnmts), which have traditionally been subdivided into the ‘de novo’ methyltransferases, Dnmt3a and Dnmt3b, and the ‘maintenance’ methyltransferase, Dnmt1. Dnmt1 maintains DNA methylation patterns and genomic stability in several in vitro cell systems, but its function in tissue-specific development, homeostasis, and disease in vivo is only beginning to be investigated.

Recently, the Kaestner lab demonstrated that loss of Dnmt1 in the adult intestinal epithelium causes a two-fold expansion of the proliferative crypt zone, indicating that Dnmt1 and DNA methylation regulate proliferative processes in the intestine. I hypothesized that loss ...


Ldb1-Mediated Complexes: A Transcriptional Paradigm That Establishes And Maintains Pancreatic Endocrine Cell Indentity, Benjamin Neal Ediger Jan 2015

Ldb1-Mediated Complexes: A Transcriptional Paradigm That Establishes And Maintains Pancreatic Endocrine Cell Indentity, Benjamin Neal Ediger

Publicly Accessible Penn Dissertations

LIM-domain-binding protein 1 (Ldb1) and the LIM-Homeodomain factor (LIM-HD) Islet-1 (Isl-1) share a robust functional relationship in directing differentiation of developmental progenitor populations. However, their mechanistic role in terminally differentiated cells is uncharacterized. In the developing endocrine pancreas, conditional ablation of either Isl-1 in the pancreatic epithelium or Ldb1 in the Pax6+ pancreatic endocrine progenitors suspended pancreatic endocrine differentiation. In light of their functional requirement in the developing endocrine pancreas, both factors remain ubiquitously enriched in the distinct, terminally differentiated endocrine cell-types that comprise the adult endocrine pancreas. To determine the requirement for Ldb1 and Isl-1 in the mature pancreatic ...


Regulation Of Adipocyte Transcription By Ppargamma Ligands, Sonia Step Jan 2014

Regulation Of Adipocyte Transcription By Ppargamma Ligands, Sonia Step

Publicly Accessible Penn Dissertations

Rosiglitazone (rosi) is a powerful insulin sensitizer, but serious toxicities have curtailed its widespread clinical use. Rosi functions as a high-affinity ligand for PPARgamma, the adipocyte-predominant nuclear receptor (NR). The classic model of NR action, involving binding of ligand to the NR on DNA, explains positive regulation of gene expression, but both ligand-dependent transcriptional repression and indirect regulation are not well understood. We have addressed these issues by studying the direct effects of rosiglitazone on gene transcription, using global run-on sequencing (GRO-seq). Rosi-induced changes in gene body transcription were pronounced after 10 minutes and correlated with steady-state mRNA levels as ...


Telomere And Proximal Sequence Analysis Using High-Throughput Sequencing Reads, Nick Stong Jan 2014

Telomere And Proximal Sequence Analysis Using High-Throughput Sequencing Reads, Nick Stong

Publicly Accessible Penn Dissertations

The telomere is a specialized simple sequence repeat found at the end of all linear chromosomes. It acts as a substrate for telomere binding factors that in coordination with other interacting elements form what is known as the shelterin complex to protect the end of the chromosome from the DNA damage repair machinery. The telomere shortens with each cell division, and once critically short is no longer able to perform this role. Short dysfunctional telomeres result in cellular senescence, apoptosis, or genome instability. Telomere length is regulated by many factors including cis-acting elements in the proximal sequence which is known ...


Regulators Of Mouse And Human Beta Cell Proliferation, Yang Jiao Jan 2013

Regulators Of Mouse And Human Beta Cell Proliferation, Yang Jiao

Publicly Accessible Penn Dissertations

Diabetes mellitus is an increasingly prevalent metabolic disorder that is estimated to affect over 300 million people by 2025. Common to either type 1 or type 2 diabetes is a progressive inadequacy of functional beta-cell mass. Recent studies have shown that during times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing beta-cell mass by beta-cell proliferation. Advances that further our knowledge of the molecular factors that control beta-cell proliferation will be crucial for understanding the homeostasis of beta-cell mass during adulthood, and are pivotal for any attempt to use instructive cues to induce the proliferation ...