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Articles 1 - 8 of 8

Full-Text Articles in Molecular Biology

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 ...


Genomic Imprinting: Establishment, Maintenance And Stability Of Dna Methylation Imprints, Lara Kimberly Abramowitz Jan 2013

Genomic Imprinting: Establishment, Maintenance And Stability Of Dna Methylation Imprints, Lara Kimberly Abramowitz

Publicly Accessible Penn Dissertations

Genomic imprinting is an epigenetic phenomenon in which genes are monoallelicaly expressed according to their parent-of-origin. Imprinted expression entails marking parental chromosomes so that a specific parental allele is stably repressed or expressed. Differential DNA methylation is essential for marking and regulating imprinted genes and is often found at imprinting control regions (ICRs). These DNA methylation imprints must be maintained throughout early development despite genome-wide epigenetic reprogramming to allow for stable allelic expression in differentiated tissues. Moreover, marking of the alleles must be erased in the germline so that establishment of sex-specific marks can occur during gametogenesis. These processes are ...


Dissecting Molecular Pathways That Underlie Disease-Causing Gata1 Mutations, Amy Erin Campbell Jan 2013

Dissecting Molecular Pathways That Underlie Disease-Causing Gata1 Mutations, Amy Erin Campbell

Publicly Accessible Penn Dissertations

Each mammalian cell type has a unique gene expression pattern that supports its specialized function. Mutations in factors that regulate gene expression can disrupt normal function and cause human disease, though the mechanistic consequences of these defects are often unknown. Here, we address how alterations in the transcription factor GATA1 lead to distinct hematologic disorders by combining structural, biochemical, and genomic approaches with gene complementation systems that examine GATA1 function in biologically relevant cellular contexts. We first investigated missense mutations in the GATA1 N-terminal zinc finger (NF) and found that NF mutations impair association with essential GATA1 cofactors. Several NF ...


Methods In And Applications Of The Sequencing Of Short Non-Coding Rnas, Paul Ryvkin Jan 2013

Methods In And Applications Of The Sequencing Of Short Non-Coding Rnas, Paul Ryvkin

Publicly Accessible Penn Dissertations

Short non-coding RNAs are important for all domains of life. With the advent of modern molecular biology their applicability to medicine has become apparent in settings ranging from diagonistic biomarkers to therapeutics and fields ranging from oncology to neurology. In addition, a critical, recent technological development is high-throughput sequencing of nucleic acids. The convergence of modern biotechnology with developments in RNA biology presents opportunities in both basic research and medical settings. Here I present two novel methods for leveraging high-throughput sequencing in the study of short non-coding RNAs, as well as a study in which they are applied to Alzheimer ...


Multiple Conserved Enhancers Of The Osteoblast Master Transcription Factor, Runx2, Integrate Diverse Signaling Pathways To Direct Expression To Developing Bone, Christopher Weber Jan 2013

Multiple Conserved Enhancers Of The Osteoblast Master Transcription Factor, Runx2, Integrate Diverse Signaling Pathways To Direct Expression To Developing Bone, Christopher Weber

Publicly Accessible Penn Dissertations

The vertebrate skeleton forms via two distinct modes of ossification, membranous and endochondral. Osteoblasts are also heterogeneous in embryonic origin; bone formed by either mode can be derived from neural crest cells or mesoderm. In contrast, all bone develops via a common genetic pathway regulated by the transcription factor Runx2. Runx2 is required for bone formation, and haploinsufficiency in humans causes the skeletal syndrome cleidocranial dysplasia, demonstrating the importance of gene dosage. Despite the central role of Runx2 in directing bone formation, little is understood about how its expression is regulated in development. We took an unbiased approach to identify ...


Regulation And Dynamic Behavior Of The Heat Shock Transcription Factor Hsf-1 In C. Elegans, Elizabeth A. Morton Jan 2013

Regulation And Dynamic Behavior Of The Heat Shock Transcription Factor Hsf-1 In C. Elegans, Elizabeth A. Morton

Publicly Accessible Penn Dissertations

Eukaryotic cells respond to heat stress by activating the transcription factor HSF1. In addition to its role in stress response, HSF1 also functions in protein homeostasis, aging, innate immunity, and cancer. Despite prominent HSF1 involvement in processes pertinent to human health and disease, there are still gaps in our understanding of HSF1. For example, controversy exists regarding the localization of HSF1, the identity of HSF1 regulators, and the function and conservation of heat-induced HSF1 stress granules. Many of the physiological roles for HSF1 have been defined using the model organism Caenorhabditis elegans, yet little is known about how the molecular ...


Abnormal Smooth Muscle Contraction Alters Gut Motility And Propagates Epithelial Invasion In The Larval Zebrafish Intestine, Joshua Abrams Jan 2013

Abnormal Smooth Muscle Contraction Alters Gut Motility And Propagates Epithelial Invasion In The Larval Zebrafish Intestine, Joshua Abrams

Publicly Accessible Penn Dissertations

Coordinated smooth muscle contraction is critical for force production and proper functioning of numerous organ systems. Activation at the myosin motor domain via phosphorylated myosin light chain (phospho-MLC) remains the primary signal to initiate contraction, but it is now appreciated that there are additional force modulators also present in smooth muscle. One particularly well studied modulatory protein is Caldesmon (CaD), which has been implicated in controlling contractile force in vascular smooth muscle, however little is known of CaD's physiological role in vivo. Studies in vitro have shown that CaD inhibits actomyosin interactions and that this effect is reversed after ...


Epigenomic And Transcriptional Regulation Of Hepatic Metabolism By Rev-Erb And Hdac3, Dan Feng Jan 2013

Epigenomic And Transcriptional Regulation Of Hepatic Metabolism By Rev-Erb And Hdac3, Dan Feng

Publicly Accessible Penn Dissertations

Metabolic activities are regulated by the circadian clock, and disruption of the clock exacerbates metabolic diseases including obesity and diabetes. Transcriptomic studies in metabolic organs suggested that the circadian clock drives the circadian expression of important metabolic genes. Here we show that histone deacetylase 3 (HDAC3) is recruited to the mouse liver genome in a circadian manner. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Diurnal recruitment of HDAC3 corresponds to the expression pattern of REV-ERBĪ±, an important component of the circadian clock. REV-ERBĪ± colocalizes with HDAC3 near genes regulating lipid ...