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Full-Text Articles in Molecular Biology

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 ...


Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude, Ryan James Cedeno Jan 2017

Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude, Ryan James Cedeno

Publicly Accessible Penn Dissertations

Epigenetic factors guide chromatin remodeling during cell state transitions and confer resistance to genotoxic stressors that could induce deleterious transformations. A particularly peculiar component of the epigenome with emerging roles in fine-tuning cell identity and upholding genomic stability is the structural histone variant macroH2A. Relatively little is currently known about macroH2A’s influence on overall cell developmental potency and less still is known about macroH2A’s contributions to adult stem cell identity and function in vivo. In this work, we use induced pluripotent stem cell (iPSC) reprogramming and the murine intestinal stem cell (ISC) system to model macroH2A’s overall ...


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 ...


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 ...


Deciphering The Tetrad Of Epigenetic Cytosine Modifications, Monica Yun Liu Jan 2016

Deciphering The Tetrad Of Epigenetic Cytosine Modifications, Monica Yun Liu

Publicly Accessible Penn Dissertations

A tetrad of epigenetic cytosine modifications imbues the DNA code with complex, dynamic meaning. DNA methyltransferase enzymes deposit methyl marks on the 5-carbon of cytosine, forming 5-methylcytosine (mC), which generally mediates long-term, locus-specific transcriptional repression during development and reprogramming. Ten-eleven translocation (TET) family enzymes oxidize the methyl group in three steps, forming predominantly 5-hydroxymethylcytosine (hmC) but also low levels of 5-formylcytosine (fC) and 5-carboxylcytosine (caC). These additional bases likely provide pathways for erasing methylation, but they may also harbor epigenetic functions in their own right. Questions regarding how each base forms and functions drive at the fundamental biology of the ...


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 ...


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 ...


The Regulation Of Gene Expression During Memory Consolidation In The Hippocampus, Shane Gary Poplawski Jan 2014

The Regulation Of Gene Expression During Memory Consolidation In The Hippocampus, Shane Gary Poplawski

Publicly Accessible Penn Dissertations

Memory consolidation is the process through which short-term memories are stabilized for long-term retention. New gene expression is required for this process to occur successfully. Although gene expression is a necessary component for memory consolidation, the targets and regulation of this gene expression are not well understood. The advent of next-generation sequencing technologies has provided a tremendous resource to probe important questions genome-wide in ways that were previously impossible. In this dissertation, I use next-generation sequencing to investigate the transcriptional targets of learning in the hippocampus. Chapter 1 reviews the previous research on the regulation of gene expression during memory ...


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 ...


Hdac3 Is A Critical Regulator Of Neural Crest Progenitor Cell Biology, Nikhil Singh Jan 2012

Hdac3 Is A Critical Regulator Of Neural Crest Progenitor Cell Biology, Nikhil Singh

Publicly Accessible Penn Dissertations

Vertebrate embryogenesis relies on the coordinated development of multiple progenitor cell pools. Specific transcriptional programs regulate the specification, expansion, migration and eventual differentiation of these progenitor cell populations, and tight control of these programs is essential for normal development to occur. Class I histone deacetylases (Hdacs), including Hdac3, play critical roles in regulating gene transcription, through both epigenetic and non-epigenetic means. In this dissertation, I use mouse genetics to explore the previously undescribed role of Hdac3 in regulating neural crest progenitor cell behavior. By genetically deleting Hdac3 in premigratory neural crest cells, I use in vivo and ex vivo techniques ...