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Identification Of Dna Methylation Episignatures For Classification And Phenotype/Genotype Correlation In Mendelian Neurodevelopmental Disorders, John Reilly Apr 2022

Identification Of Dna Methylation Episignatures For Classification And Phenotype/Genotype Correlation In Mendelian Neurodevelopmental Disorders, John Reilly

Electronic Thesis and Dissertation Repository

ABSTRACT: Diagnosis for neurodevelopmental disorders poses numerous challenges, related to the lack of specific findings and limited understanding of clinical impact of the majority of genetic variation. Epigenomics mechanisms involve chemical modifications in DNA that involve a range of cellular mechanisms. DNA methylation is an epigenetic mechanism involving addition and removal of methyl groups to cytosine residues. These methylation signals form episignatures; patterns of methylation that can be used as biomarkers capable of differentiating neurodevelopmental disorders. EpiSigns have enabled molecular diagnosis of a number of genetic conditions, classification of variants of unknown significance, and provided insights into the pathophysiology of …


Nucleoporin-Mediated Regulation Of The Kcnq1ot1 Imprinted Domain, Saqib Sachani Aug 2016

Nucleoporin-Mediated Regulation Of The Kcnq1ot1 Imprinted Domain, Saqib Sachani

Electronic Thesis and Dissertation Repository

Genomic imprinting is an epigenetic phenomenon that restricts gene expression to one parental allele while the other copy is silent. How this duality is regulated is not fully understood. Using the Kcnq1ot1 imprinted domain as a model, previous work in the laboratory identified nucleoporin 107 as a candidate regulator of imprinted domain regulation. Within the Kcnq1ot1 domain resides the imprinting control region, the paternally expressed Kcnq1ot1 (Kcnq1 opposite transcript 1) noncoding RNA, nine maternal-expressed protein-coding genes, as well as genes that escape imprint regulation. On the maternal allele, the Kcnq1ot1 imprinting control region is methylated, silencing the embedded Kcnq1ot1 …


Elucidating The Role Of Hdac8 In Anthrax Lethal Toxin-Induced Pyroptosis And Cytokine Gene Silencing In Macrophages, Chantelle M. Reid Apr 2015

Elucidating The Role Of Hdac8 In Anthrax Lethal Toxin-Induced Pyroptosis And Cytokine Gene Silencing In Macrophages, Chantelle M. Reid

Electronic Thesis and Dissertation Repository

Anthrax is a lethal infectious disease caused by the bacterium Bacillus anthracis. B. anthracis secretes the virulence factor anthrax lethal toxin (LeTx), which causes rapid cell death known as pyroptosis and immune suppression in macrophages. Strikingly, RAW 264.7 macrophages pre-exposed to sub-lethal doses of LeTx become refractory to subsequent high cytolytic doses. The phenomenon is termed toxin-induced resistance (TIR). TIR is in part linked to the down-regulation of three mitochondrial death genes, BCL2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), BNIP3-like (BNIP3L), and metastatic lymph node 64 (MLN64) protein, as well as the up-regulation …


Cellular Adaptation Of Macrophages To Anthrax Lethal Toxin-Induced Pyroptosis Via Epigenetic Mechanisms, Chae Young Han Apr 2013

Cellular Adaptation Of Macrophages To Anthrax Lethal Toxin-Induced Pyroptosis Via Epigenetic Mechanisms, Chae Young Han

Electronic Thesis and Dissertation Repository

Cellular adaptation to microbial stresses has been demonstrated in several cell types. Macrophages (MФ) are sentinel immune cells fending off invading microbes. Anthrax lethal toxin (LeTx) is a key virulence factor released by Bacillus anthracis that causes rapid cell death, pyroptosis. A small number of RAW246.7 macrophages (~4%) exposed to a non-lethal dose of LeTx become resistant to LeTx-induced pyroptosis for ~ 4 weeks, termed “toxin-induced resistance (TIR)”. Here, I showed that high levels of DNA methyl transferase1 (DNMT1) expression were maintained although global genomic methylation levels were not high in TIR. TIR cells treated with the DNMT inhibitor 5-azacitidine …