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Full-Text Articles in Molecular Biology

All The Right Noises: Causes And Consequences Of Stochastic Trimethylamine Oxide Reductase Expression In Escherichia Coli, Jeffrey Carey Jan 2018

All The Right Noises: Causes And Consequences Of Stochastic Trimethylamine Oxide Reductase Expression In Escherichia Coli, Jeffrey Carey

Publicly Accessible Penn Dissertations

Microbial populations can maximize fitness in dynamic environments through bet hedging, a process wherein a subpopulation assumes a phenotype not optimally adapted to the present environment but well adapted to an environment likely to be encountered. Here we show that oxygen induces fluctuating expression of the trimethylamine oxide (TMAO) respiratory system of Escherichia coli, diversifying the cell population and enabling a bet-hedging strategy that permits growth following oxygen loss. This regulation by oxygen affects the variance in gene expression but leaves the mean unchanged. We show that the oxygen-sensitive transcription factor IscR is the key regulator of variability. Oxygen causes ...


Exploring The Role Of Tet1 In Genomic Imprinting, Jennifer Myers Sanmiguel Jan 2018

Exploring The Role Of Tet1 In Genomic Imprinting, Jennifer Myers Sanmiguel

Publicly Accessible Penn Dissertations

DNA methylation is an essential epigenetic mark crucial for normal mammalian development. This modification controls the expression of a unique class of genes, designated as imprinted, which are expressed monoallelically and in a parent-of-origin-specific manner. Proper parental allele-specific DNA methylation at imprinting control regions (ICRs) is necessary for appropriate imprinting. Processes that deregulate DNA methylation of imprinted loci cause disease in humans. DNA methylation patterns dramatically change during mammalian development: first, the majority of the genome, with the exception of ICRs, is demethylated after fertilization, and subsequently undergoes genome-wide de novo DNA methylation. Secondly, after primordial germ cells are specified ...


Elucidating The Role Of Hepatic Ppp1r3b In Glucose And Lipid Metabolism, Minal B. Mehta Jan 2017

Elucidating The Role Of Hepatic Ppp1r3b In Glucose And Lipid Metabolism, Minal B. Mehta

Publicly Accessible Penn Dissertations

Genetic variants mapping to chromosome 8p23.1 have been associated with multiple metabolic traits in humans, including plasma constituents (glucose, lactate, insulin, HDL and non-HDL cholesterol), and hepatic steatosis with genome-wide significance. The closest gene of known function, PPP1R3B, (Protein Phosphatase 1 Regulatory Subunit 3B), encodes a protein (GL) that is known to regulate glycogen metabolism. We sought to test the hypothesis that hepatic PPP1R3B is the causal gene underlying the human genetic association with these metabolic attributes and to understand the mechanisms. We generated two separate mice with liver-specific deletion (Ppp1r3b∆hep) or liver-specific overexpression of Ppp1r3b. Hepatic deletion ...


Dna Double Strand Breaks Suppress Expression Of The Rag Recombinase: Mechanisms And Consequences, Megan Rose Fisher Jan 2017

Dna Double Strand Breaks Suppress Expression Of The Rag Recombinase: Mechanisms And Consequences, Megan Rose Fisher

Publicly Accessible Penn Dissertations

Developing B and T lymphocytes must rearrange the genomic sequence of antigen receptor genes by V(D)J recombination. The lymphocyte-specific endonuclease RAG, composed of Rag1 and Rag2, initiates this process by cleaving specific sites within antigen receptor loci. RAG expression must be carefully regulated to ensure that V(D)J recombination occurs only under appropriate circumstances. The Bassing laboratory has previously demonstrated that Igκ locus cleavage by RAG in pre-B cells initiates a feedback-inhibition signal suppressing RAG expression. Here, we show that DNA double strand breaks (DSBs) induced by a variety of genotoxic agents have a similar effect in ...


Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu Jan 2016

Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu

Publicly Accessible Penn Dissertations

The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute to the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 ...


Determination Of A Comprehensive Alternative Splicing Regulatory Network And The Combinatorial Regulation By Key Factors During The Epithelial To Mesenchymal Transition, Yueqin Yang Jan 2016

Determination Of A Comprehensive Alternative Splicing Regulatory Network And The Combinatorial Regulation By Key Factors During The Epithelial To Mesenchymal Transition, Yueqin Yang

Publicly Accessible Penn Dissertations

The epithelial to mesenchymal transition (EMT) is a process by which epithelial cells transdifferentiate into mesenchymal cells. It is essential for embryonic development and implicated in cancer metastasis. While the transcriptional regulation of EMT has been well-studied, the role of post-transcriptional regulation, particularly alternative splicing (AS) regulation in EMT, remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins ESRP1 and ESRP2 are important for regulation of many AS events that altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the splicing regulatory network in EMT require further investigation.

In the first part of ...


Iron-Induced Complement Dysregulation In The Retinal Pigment Epithelium: Implications For Age-Related Macular Degeneration, Yafeng Li Jan 2015

Iron-Induced Complement Dysregulation In The Retinal Pigment Epithelium: Implications For Age-Related Macular Degeneration, Yafeng Li

Publicly Accessible Penn Dissertations

Age-related macular degeneration (AMD), typically manifesting as a loss of central vision in elderly persons, is a leading cause of blindness in highly developed nations. AMD is a multifactorial disease associated with aging, oxidative stress, complement dysregulation, dsRNA toxicity, among many other possible factors. The formation of extracellular deposits, termed drusen, below the retinal pigment epithelial (RPE) cell layer in the outer retina is a pathognomonic hallmark of AMD. The composition of drusen is complex, but identified elements include iron, complement components, and amyloid protein derivatives. This suggests that iron may be involved in the pathophysiology of AMD. Further support ...


Cell Biology Of Cheating - Mechanisms Of Chromosome Segregation During Female Meiosis, Lukas Chmatal Jan 2015

Cell Biology Of Cheating - Mechanisms Of Chromosome Segregation During Female Meiosis, Lukas Chmatal

Publicly Accessible Penn Dissertations

Karyotype, chromosome number and composition, is a basic characteristic of species and its changes are frequently associated with speciation. Karyotype conversion, from mostly telocentric (centromere terminal) to mostly metacentric (centromere internal), typically reflects fixation of Robertsonian (Rb) fusions, a common chromosomal rearrangement that joins two telocentric chromosomes at their centromeres to create one metacentric. Fixation of Rb fusions can be explained by meiotic drive: biased chromosome segregation during female meiosis. However, there is no mechanistic explanation of why fusions preferentially segregate to the egg in some populations, leading to fixation and karyotype change, while other populations preferentially eliminate the fusions ...


Controlling Thermogenesis: Understanding The Role Of Prdm16 In The Development And Function Of Brown Fat, Matthew James Harms Jan 2015

Controlling Thermogenesis: Understanding The Role Of Prdm16 In The Development And Function Of Brown Fat, Matthew James Harms

Publicly Accessible Penn Dissertations

The alarming rise in the incidence of obesity found throughout the world has precipitated a need to look for novel methods to increase energy expenditure to counter weight gain. Recently it was discovered that adult humans possess a substantial mass of brown adipose tissue (BAT), a tissue that consumes stored lipid to produce heat. Although the primary physiologic role for BAT is to protect mammals from the cold, it is currently thought that enhancing BAT mass or activating BAT in humans is a novel way to decrease adiposity. However, before BAT can be effectively utilized for therapeutic purposes a better ...


The Identification Of Novel Mechanisms In Neuronal Development And Degeneration, Angela Marie Jablonski Jan 2015

The Identification Of Novel Mechanisms In Neuronal Development And Degeneration, Angela Marie Jablonski

Publicly Accessible Penn Dissertations

The goal of this dissertation is to further understand two key, broad processes which occur over the course of a neuron's lifetime: its development and possible degeneration in disease. We identify novel components in both of these processes and attempt to understand the functional significance as well as the mechanism each component uses to exert its effects.

We begin with work done focusing on how the neuron's dendritic tree develops. The development of neurons has two phases: (1) a first phase relying on a genetic program and (2) a second phase that uses synaptic activity to guide the ...


Inducible Protein Dimerization: New Tools And Applications To Understanding The Mitotic Checkpoint, Edward Raymond Ballister Jan 2014

Inducible Protein Dimerization: New Tools And Applications To Understanding The Mitotic Checkpoint, Edward Raymond Ballister

Publicly Accessible Penn Dissertations

Cellular processes such as growth, migration, signaling and cell division require choreographed interactions between dozens or hundreds of proteins carefully organized in time and space. In order to test hypotheses about complex cellular functions, it is desirable to experimentally perturb the interactions of individual proteins that perform these functions with a level of spatial and temporal control commensurate with the time and space scales over which the system is naturally organized. Inducible protein dimerization offers the ability to experimentally control protein-protein interactions. Inducible dimerization can be used to test the immediate effects of dimerizing two proteins, or it can be ...


The Application And Challenges Of Rna-Sequencing To The Study Of Circadian Rhythms, Nicholas Lahens Jan 2014

The Application And Challenges Of Rna-Sequencing To The Study Of Circadian Rhythms, Nicholas Lahens

Publicly Accessible Penn Dissertations

The circadian clock drives daily rhythms in behavior and physiology, often in anticipation of the coming dusk or dawn. Almost all organisms possess an internal time-keeper, as it represents an adaptation to one of the most ancient selective pressures; the day-night cycle. Mounting evidence suggests the clock plays important roles in critical metabolic and signalling pathways, the sleep/wake cycle, immune function, as well as learning and memory. Perhaps more importantly, misregulation of the clock is associated with metabolic disorders, neurodegeneration, and incidence of cancer. In an effort to unlock the connections between the circadian clock and these downstream effects ...


A Chemical-Genetic Screen For Identifying Substrates Of The Er Kinase Perk, Nancy L. Maas Jan 2014

A Chemical-Genetic Screen For Identifying Substrates Of The Er Kinase Perk, Nancy L. Maas

Publicly Accessible Penn Dissertations

Cells constantly encounter changing environments that challenge the ability to adapt

and survive. Signal transduction networks enable cells to appropriately sense and respond

to these changes, and are often mediated through the activity of protein kinases. Protein

kinases are a class of enzyme responsible for regulating a broad spectrum of cellular

functions by transferring phosphate groups from ATP to substrate proteins, thereby

altering substrate activity and function. PERK is a resident kinase of the endoplasmic

reticulum, and is responsible for sensing perturbations in the protein folding capacity of

the ER. When the influx of unfolded, nascent proteins exceeds the folding ...


Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe Jan 2013

Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe

Publicly Accessible Penn Dissertations

microRNAs (miRNAs) are 20~24nt small RNAs that are critical for many biological aspects, from development to age-associated processes. Starting from the identification of the first miRNA, lin-4, hundreds of miRNAs have been discovered across species. To reveal the role of miRNAs in aging, studies have profiled changes in miRNA levels with age. However, increasing evidence suggests that miRNAs show heterogeneity in length and sequence in different biological contexts. Despite the observation of such heterogeneity, it is largely unknown how such heterogeneity is generated, and whether it is biologically regulated or important. Here we report the characterization of a novel ...


Higher-Order Chromatin Organization In Hematopoietic Transcription, Wulan Deng Jan 2012

Higher-Order Chromatin Organization In Hematopoietic Transcription, Wulan Deng

Publicly Accessible Penn Dissertations

Coordinated transcriptional networks underlie complex developmental processes. Transcription factors play central roles in such networks by binding to core promoters and regulatory elements and thereby controlling transcription activities and chromatin states in the genome. GATA1 is a hematopoietic transcription factor that controls multiple hematopoietic lineages by activating and repressing gene expression, yet the in vivo mechanisms that specify these opposing activities are unknown. By examining the composition of GATA1 associated protein complexes in a genetic complementary erythroid cell system as well as through the use of tiling arrays, we found that a multi-protein complex containing SCL/TAL1, LMO2, Ldb1, and ...


Evolution Of Molecular Function In Mammalian Neurons, Chantal Francis Dec 2011

Evolution Of Molecular Function In Mammalian Neurons, Chantal Francis

Publicly Accessible Penn Dissertations

A common question in neuroscience is what forms the neurological basis of the variety of behaviors in mammals. While many studies have compared mammalian anatomy and evolution, few have investigated the physiologic functions of individual neurons in a comparative manner. Neurons’ ability to modify their features in response to stimuli, known as synaptic plasticity, is fundamental for learning and memory. A key feature of synaptic plasticity involves delivering mRNA to distinct domains where they are locally translated. Regulatory coordination of these events is critical for synaptogenesis and synaptic plasticity as defects in these processes can lead to neurological diseases. In ...


Role And Regulation Of Myosin Iia In Natural Killer Cell Cytotoxicity, Keri Sanborn Aug 2011

Role And Regulation Of Myosin Iia In Natural Killer Cell Cytotoxicity, Keri Sanborn

Publicly Accessible Penn Dissertations

Natural killer (NK) cells are lymphocytes of the innate immune system that provide defense by directing their cytotoxic activity against virally infected and tumorigenic cells. Target cell lysis requires directed secretion of lytic granule contents, including pore-forming perforin and apoptosis-inducing granzymes, at the contact site. During the formation of a mature immunological synapse (IS) with a target cell, an NK cell polymerizes filamentous actin (F-actin) at the contact site, which may serve as a barrier to secretion of lytic granules for cytotoxicity. An actin-based motor protein, nonmuscle myosin IIA, has been demonstrated to be required for NK cell cytotoxic activity ...


Decoding Cytochrome C Oxidase Biogenesis: New Insights Into Copper Trafficking, Nursel Seda Ekici Jan 2011

Decoding Cytochrome C Oxidase Biogenesis: New Insights Into Copper Trafficking, Nursel Seda Ekici

Publicly Accessible Penn Dissertations

Acquisition, delivery and incorporation of metals to their respective metalloproteins are important cellular processes. These processes are tightly controlled so that cells are not exposed to free metal concentrations that would lead to harmful oxidative damages. Cytochrome c oxidases (Cox) are among these metalloproteins whose assembly and activity involves incorporation of Cu cofactor into their catalytic subunits in addition to the maturation of other subunits. In this study, we focused on the pathways of acquisition of Cu by the facultative phototroph Rhodobacter capsulatus for incorporation into the heme–Cu binuclear center of its cbb3–type Cox (cbb3–Cox ...