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Chromatin Dynamics In Pluripotency And Differentiation: A Dissertation, Ozlem Yildirim May 2012

Chromatin Dynamics In Pluripotency And Differentiation: A Dissertation, Ozlem Yildirim

GSBS Dissertations and Theses

Different cell types in multi-cellular organisms heritably maintain different gene expression patterns despite carrying the same genome; a phenomenon termed epigenetics. It is widely believed that the packaging state of the genome, known as chromatin structure, carries epigenetic information. How chromatin states are inherited and how chromatin structure changes during development, moreover how different epigenomes, such as chromatin and DNA modifications communicate with each other during these processes are important questions. Accordingly, understanding the mechanisms that govern pluripotency and differentiation requires details of chromatin dynamics. The major goal of my doctoral thesis was to understand the genome wide view of ...


Regulation Of Cancer Cell Survival Mediated By Endogenous Tumor Suppression: A Dissertation, Minakshi Guha Jul 2009

Regulation Of Cancer Cell Survival Mediated By Endogenous Tumor Suppression: A Dissertation, Minakshi Guha

GSBS Dissertations and Theses

Cancer is the second leading cause of death among men and women after heart disease. Though our knowledge associated with the complexities of the cancer network has significantly improved over the past several decades, we have only recently started to get a more complete molecular understanding of the disease. To better comprehend signaling pathways that prevent disease development, we focused our efforts on investigating endogenous tumor suppression networks in controlling effectors of cancer cell survival and proliferation. Survivin is one such effector molecule that controls both cell proliferation and survival. In order to identify how this protein is overexpressed in ...


Analysis Of Long-Range Chromosomal Interactions In Saccharomyces Cerevisiae: A Dissertation, Adriana Miele Apr 2009

Analysis Of Long-Range Chromosomal Interactions In Saccharomyces Cerevisiae: A Dissertation, Adriana Miele

GSBS Dissertations and Theses

Long-range chromosomal interactions have been discovered in a number of organisms, suggesting that gene regulation through direct physical association with regulatory elements and/or other genes is a common and conserved phenomenon. This thesis investigates the relationship between direct physical contact of genomic loci and how these interactions may play a role in gene regulation. Analysis of such levels of chromosomal organization has been made possible in part by the emergence of Chromosome Conformation Capture (3C). This technique makes use of formaldehyde crosslinking to trap interacting chromosomal fragments, which can be detected after a number of manipulations. By adapting the ...


Delineating The C. Elegans Microrna Regulatory Network: A Dissertation, Natalia Julia Martinez Apr 2009

Delineating The C. Elegans Microrna Regulatory Network: A Dissertation, Natalia Julia Martinez

GSBS Dissertations and Theses

Metazoan genomes contain thousands of protein-coding and non-coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans-regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis-regulatory DNA elements that are often located in or near their target genes, while microRNAs hybridize to cis-regulatory RNA elements mostly located in the 3’ untranslated region (3’UTR) of their target mRNAs.

My work in the ...


Recombinational Repair Of A Chromosomal Dna Double Strand Break: A Dissertation, Manisha Sinha Mar 2009

Recombinational Repair Of A Chromosomal Dna Double Strand Break: A Dissertation, Manisha Sinha

GSBS Dissertations and Theses

Repairing a chromosomal DNA double strand break is essential for survival and maintenance of genomic integrity of a eukaryotic organism. The eukaryotic cell has therefore evolved intricate mechanisms to counteract all sorts of genomic insults in the context of chromatin structure. Modulating chromatin structure has been crucial and integral in regulating a number of conserved repair processes along with other fundamental genomic processes like replication and transcription.

The work in this dissertation has focused on understanding the role of chromatin remodeling enzymes in the repair of a chromosomal DNA double strand break by homologous recombination. This has been approached by ...


Chromatin Remodeling And Transcriptional Memory: A Dissertation, Sharmistha Kundu Dec 2008

Chromatin Remodeling And Transcriptional Memory: A Dissertation, Sharmistha Kundu

GSBS Dissertations and Theses

Transcriptional regulation of gene expression is critical for all unicellular and multicellular organisms. The ability to selectively induce or repress expression of only a few genes from the entire genome gives cells the ability to respond to changing environmental conditions, grow and proliferate. Multicellular organisms begin life as a single totipotent cell, which undergoes many cell divisions during embryonic and later postnatal development. During this process, the dividing cells of the embryo progressively lose their pluripotency and adopt restricted cell fates. Cell fate restriction leads different cell types to gain unique transcriptional profiles. This transcriptional profile or gene expression pattern ...


Epigenetic Determinants Of Altered Gene Expression In Schizophrenia: A Dissertation, Hsien-Sung Huang May 2008

Epigenetic Determinants Of Altered Gene Expression In Schizophrenia: A Dissertation, Hsien-Sung Huang

GSBS Dissertations and Theses

Schizophrenia is a neurodevelopmental disorder affecting 1% of the general population. Dysfunction of the prefrontal cortex (PFC) is associated with the etiology of schizophrenia. Moreover, a substantial deficit of GAD1mRNA in schizophrenic PFC has been reported by different groups. However, the underlying molecular mechanisms are still unclear. Interestingly, epigenetic factors such as histone modifications and DNA methylation could be involved in the pathogenesis of schizophrenia during the maturation of the PFC. In my work, I identified potential epigenetic changes in schizophrenic PFC and developmental changes of epigenetic marks in normal human PFC. Furthermore, mouse and neuronal precursor cell models ...


Epigenetic Telomere Protection By Drosophila Dna Damage Response Pathways: A Dissertation, Sarah R. Oikemus Sep 2006

Epigenetic Telomere Protection By Drosophila Dna Damage Response Pathways: A Dissertation, Sarah R. Oikemus

GSBS Dissertations and Theses

Several aspects of Drosophila telomere biology indicate that telomere protection can be regulated by an epigenetic mechanism. First, terminally deleted chromosomes can be stably inherited and do not induce damage responses such as apoptosis or cell cycle arrest. Second, the telomere protection proteins HP1 and HOAP localize normally to these chromosomes and protect them from fusions. Third, unprotected telomeres still contain HeT-A sequences at sites of fusions. Taken together these observations support a model in which an epigenetic mechanism mediated by DNA damage response proteins protects Drosophilatelomeres from fusion.

Work presented in this thesis demonstrates that the Drosophila proteins ...


Human Rad51: Regulation Of Cellular Localization And Function In Response To Dna Damage: A Dissertation, Brian Thomas Bennett Feb 2006

Human Rad51: Regulation Of Cellular Localization And Function In Response To Dna Damage: A Dissertation, Brian Thomas Bennett

GSBS Dissertations and Theses

Repair of DNA double-strand breaks via homologous recombination is an essential pathway for vertebrate cell development and maintenance of genome integrity throughout the organism’s lifetime. The Rad51 enzyme provides the central catalytic function of homologous recombination while many other proteins are involved in regulation and assistance of Rad51 activity, including a group of five proteins referred to as Rad51 paralogs (Rad51B, Rad51C, Rad51D, Xrcc2, Xrcc3). At the start of my work, cellular studies of human Rad51 (HsRad51) had shown only that it forms distinct nuclear foci in response to DNA damage. Additionally, no information regarding the cellular localization, potential ...


The Roles Of Dna Mismatch Repair And Recombination In Drug Resistance: A Dissertation, Melissa A. Calmann Dec 2004

The Roles Of Dna Mismatch Repair And Recombination In Drug Resistance: A Dissertation, Melissa A. Calmann

GSBS Dissertations and Theses

Cells have evolved different pathways in order to tolerate damage produced by different cytotoxic agents. Each agent reacts differently with DNA causing formation of different types of adducts, each eliciting the SOS stress response to induce different cellular repair pathways. One such type of substrate generated by cytotoxic agents is the DNA double strand break (DSB). The main pathway to repair such damage in the cell is through a process of recombination. In this thesis, I specifically examined the anti-cancer therapeutic agent cisplatin, which forms single- and double-strand breaks in DNA, and methylating agents, which are proposed to also be ...


Chondrocyte Adhesion To Rgd-Bonded Alginate: Effect On Mechanotransduction And Matrix Metabolism: A Dissertation, Nicholas G. Genes Aug 2003

Chondrocyte Adhesion To Rgd-Bonded Alginate: Effect On Mechanotransduction And Matrix Metabolism: A Dissertation, Nicholas G. Genes

GSBS Dissertations and Theses

The mechanism of mechanotransduction in chondrocyte matrix metabolism is not well understood, in part because of the density of cartilage and in part because of limitations in in vitroculture systems. Using alginate covalently modified to include the integrin adhesion ligand R-G-D (arginine-glycine-aspartate) represents a unique approach to studying mechanotransduction in that it allows for exploration of the role of integrin adhesion in mediating changes to chondrocyte behavior.

The hypothesis of this research was that chondrocytes will form a cytoskeletal adhesion to RGD-alginate mediated integrins, that this attachment will enable chondrocyte sensation of mechanical signals, and this signaling will alter ...


Mechanistic Analysis Of Chromatin Remodeling Enzymes: A Dissertation, Mariela Jaskelioff May 2003

Mechanistic Analysis Of Chromatin Remodeling Enzymes: A Dissertation, Mariela Jaskelioff

GSBS Dissertations and Theses

The inherently repressive nature of chromatin presents a sizeable barrier for all nuclear processes in which access to DNA is required. Therefore, eukaryotic organisms ranging from yeast to humans rely on a battery of enzymes that disrupt the chromatin structure as a means of regulating DNA transactions.

These enzymes can be divided into two broad classes: those that covalently modify histone proteins, and those that actively disrupt nucleosomal structure using the free energy derived from ATP hydrolysis. The latter group, huge, multisubunit ATP-dependent chromatin remodeling factors, are emerging as a common theme in all nuclear processes in which access to ...


Intranuclear Trafficking Of Runx/Aml/Cbfa/Pebp2 Transcription Factors In Living Cells: A Dissertation, Kimberly Stacy Harrington Mar 2003

Intranuclear Trafficking Of Runx/Aml/Cbfa/Pebp2 Transcription Factors In Living Cells: A Dissertation, Kimberly Stacy Harrington

GSBS Dissertations and Theses

The family of runt related transcription factors (RUNX/Cbfa/AML/PEBP2) are essential for cellular differentiation and fetal development. RUNX factors are distributed throughout the nucleus in punctate foci that are associated with the nuclear matrix/scaffold and generally correspond with sites of active transcription. Truncations of RUNX proteins that eliminate the C-terminus including a 31-amino acid segment designated the nuclear matrix targeting signal (NMTS) lose nuclear matrix association and result in lethal hematopoietic (RUNX1) and skeletal (RUNX2) phenotypes in mice. These findings suggest that the targeting of RUNX factors to subnuclear foci may mediate the formation of multimeric regulatory ...


Mechanisms Contributing To Transcriptional Regulation And Chromatin Remodeling Of The Bone Specific Osteocalcin Gene, Soraya Elisa Gutierrez Gallegos Nov 2002

Mechanisms Contributing To Transcriptional Regulation And Chromatin Remodeling Of The Bone Specific Osteocalcin Gene, Soraya Elisa Gutierrez Gallegos

GSBS Dissertations and Theses

Activation of tissue-specific genes is a tightly controlled process that normally involves the combined action of several transcription factors and transcriptional co-regulators. The bone-specific osteoca1cin gene (OC) has been used as a prototype to study both tissue-specific and hormonal responsiveness. In this study we have examined the role of Runx2, VDR and C/EBP factors in the regulation of OC gene transcription. Contributions of the Runx and VDRE motifs to OC promoter activity were addressed by introducing point mutations within the context of the rat (-1.1 kb) osteocalcin promoter fused to a CAT-reporter gene. The functional significance of these ...


The Human Rad52 Protein: A Correlation Of Protein Function With Oligomeric State: A Dissertation, Janice A. Lloyd Sep 2002

The Human Rad52 Protein: A Correlation Of Protein Function With Oligomeric State: A Dissertation, Janice A. Lloyd

GSBS Dissertations and Theses

The regulation of protein function through oligomerization is a common theme in biological systems. In this work, I have focused on the effects of the oligomeric states of the human Rad52 protein on activities related to DNA binding. HsRad52, a member of the RAD52 epistasis group, is thought to play an important and as yet undefined role in homologous recombination. HsRad52 preferentially binds to ssDNA over dsDNA and stimulates HsRad51-mediated strand exchange (Benson et al., 1998). In either the presence or absence of DNA, HsRad52 has been observed to form both 10 nm ring-like structures as well as higher ...


A Characterization Of Substrates And Factors Involved In Yeast Nonsense-Mediated Mrna Decay: A Dissertation, Jonathan Philip Belk Jan 2002

A Characterization Of Substrates And Factors Involved In Yeast Nonsense-Mediated Mrna Decay: A Dissertation, Jonathan Philip Belk

GSBS Dissertations and Theses

Many intricate and highly conserved mechanisms have evolved to safeguard organisms against errors in gene expression. The nonsense-mediated mRNA decay pathway (NMD) exemplifies one such mechanism, specifically by eliminating mRNAs containing premature translation termination codons within their protein coding regions, thereby limiting the synthesis of potentially deleterious truncated polypeptides. Studies in Saccharomyces Cerevisiae have found that the activity of at least three trans-acting factors, known as UPF1, UPF2/NMD2, and UPF3is necessary for the proper function of the NMD pathway. Further research conducted in yeast indicates that the degradation of substrates of the NMD pathway is dependent on ...


Allosteric Regulation Of Recombination Enzymes E. Coli Reca And Human Rad51: A Dissertation, Julie Kelley De Zutter Aug 2000

Allosteric Regulation Of Recombination Enzymes E. Coli Reca And Human Rad51: A Dissertation, Julie Kelley De Zutter

GSBS Dissertations and Theses

ATP plays a critical role in the regulation of many enzyme processes. In this work, I have focused on the ATP mediated regulation of the recombination processes catalyzed by the E. coliRecA and the human Rad51 proteins. The RecA protein is a multifunctional enzyme, which plays a central role in the processes of recombinational DNA repair, homologous genetic recombination and in the activation of the cellular SOS response to DNA damage. Each of these functions requires a common activating step, which is the formation of a RecA-ATP-ssDNA nucleoprotein filament. The binding of ATP results in the induction of a ...


Mrna Poly(A) Tail: A 3' Enhancer Of Translational Initiation: A Thesis, David Munroe Jan 1999

Mrna Poly(A) Tail: A 3' Enhancer Of Translational Initiation: A Thesis, David Munroe

GSBS Dissertations and Theses

Most eukaryotic mRNAs have a sequence of polyadenylic acid [poly(A)] at their 3'-termini. Although it has been almost two decades since the discovery of these poly(A) tracts, their function(s) have yet to be clarified. Earlier results from our laboratory led us to propose that poly(A) has a role in translation. More specifically, we proposed that an interaction of the cytoplasmic poly(A)-binding protein (PABP) with a critical minimum length of poly(A) facilitates the initiation of translation of poly(A)+, but not poly(A)-, mRNAs. The results of several different experimental approaches have provided ...


Development And Application Of Ultrastructural In Situ Hybridization To Visualize The Spatial Organization Of Mrna: A Dissertation, Gary J. Bassell Sep 1992

Development And Application Of Ultrastructural In Situ Hybridization To Visualize The Spatial Organization Of Mrna: A Dissertation, Gary J. Bassell

GSBS Dissertations and Theses

It has been well documented that mRNA is associated with the cytoskeleton, and that this relationship is involved in translation and mRNA sorting. The molecular components involved in the attachment of mRNA to the cytoskeleton are only poorly understood. The objective of this thesis was to directly visualize the interaction of mRNA with the cytoskeleton, with sufficient resolution to identify the filament systems and structures involved. This work required the development of novel in situ hybridization methods for use with electron microscopy. This allowed resolution to visualize single mRNA molecules and individual filaments.

The development of a silver enhancement methodology ...


Transcriptional Control Of Human Histone Gene Expression: Delineation And Regulation Of Protein/Dna Interactions: A Thesis, Andre John Van Wijnen May 1991

Transcriptional Control Of Human Histone Gene Expression: Delineation And Regulation Of Protein/Dna Interactions: A Thesis, Andre John Van Wijnen

GSBS Dissertations and Theses

Transcriptional regulation of cell cycle controlled genes is fundamental to cell division in eukaryotes and a broad spectrum of physiological processes directly related to cell proliferation. Expression of the cell cycle dependent human H4, H3 and H1 histone genes is coordinately regulated at both the transcriptional and posttranscriptional levels. We have systematically analyzed the protein/DNA interactions of the immediate 5'regions of three prototypical cell cycle controlled histone genes, designated H4-F0108, H3-ST519 and H1-FNC16, to define components of the cellular mechanisms mediating transcriptional regulation.

Multiple biochemically distinct protein/DNA interactions were characterized for each of these genes, and the ...