Cis-regulatory Mechanisms of Acute Phase Gene Expression

Download or read book Cis-regulatory Mechanisms of Acute Phase Gene Expression written by Minggao Liang and published by . This book was released on 2021 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The accurate control of when and where genes are expressed is central to our understanding of development and disease. Elucidating the mechanisms that control this complex, multifaceted process is a major endeavor at the forefront of genetics and genome biology. The acute phase response (APR) is an evolutionarily conserved systemic response to inflammation that triggers rapid gene expression changes in the liver and other tissues. Genes induced during the APR are regulated via unique mechanisms that facilitate their rapid expression upon stimulation while maintaining their silencing under basal conditions. To dissect the mechanisms controlling APR gene expression, I employ a combination of epigenetic profiling, comparative genomics, and chromatin conformation capture to characterize the cis-regulation of a representative APR gene, PLAU. I investigate how PLAU is dysregulated in Quebec platelet disorder, a bleeding disorder in which a single tandem-duplication of PLAU causes its ectopic >100-fold overexpression in platelets and megakaryocytes. I demonstrate that the silencing of PLAU is normally facilitated by local 3-dimensional (3D) chromatin architecture which isolates it from the activity of nearby tissue-specific enhancers, while disruption of this architecture in QPD results in ectopic activation of PLAU by a conserved megakaryocyte enhancer. Employing a similar multi-omics approach, I investigate genome-wide transcriptional and epigenetic changes during the APR in the context of 3D chromatin architecture in the mouse liver. I demonstrate that enhancer-gene pairs within the same chromatin loop are more likely to show concordant changes in gene expression than equidistant genes in different domains, together illustrating a paradigm in which 3D chromatin architecture coordinates both the activation and silencing of acute-phase gene expression.