Investigation into the effect of RNASEH2B mutation on R-loop dysregulation in the pathogenesis of Aicardi-Goutières syndrome (AGS) Público

Abstract

R-loop is a three-stranded structure composed of a DNA:RNA hybrid and a displaced single- stranded DNA. Unscheduled R-loops level will lead to DNA damage and genome instability. To maintain R-loop homeostasis, the RNASEH2 gene can resolve excessive R-loop by cleaving RNA strands from R-loops. Clinically, more than 50% of diagnosed patients with Aicardi-Goutières syndrome (AGS), a severe autosomal recessive inflammatory disease that affects a patient’s neurological development when born, have been found to have the mutation in RNASEH2 gene. However, the mechanism of mutations in RNASEH2 in the pathogenesis of AGS remains unclear. RNASEH2B is a subunit of RNASEH2, that we focused on in this study to examine its effect on R-loop regulation. Using the human iPSC-derived neuron method, we successfully characterized iPSC from an AGS patient’s PBMC and differentiated it into neurons. An increased R-loop level was shown in the AGS patient. Using DRIP-seq, we profiled genome-wide R-loop and identified differential R-loop peaks in the AGS patient. We also found that upregulated R- loop peaks fall in the intergenic regions and downregulated R-loop peaks fall in the gene body regions. Altogether, our data suggest that mutation in RNASEH2B may cause R-loop dysregulation, ultimately leading to AGS.

Table of Contents

Introduction..................................................................................................................................................1 Results..........................................................................................................................................................3 Discussion....................................................................................................................................................12 Methods.......................................................................................................................................................14 References....................................................................................................................................................17

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Genetics
Palavra-chave	R-loop Aicardi-Goutières syndrome
Committee Chair / Thesis Advisor	Dr. Bing Yao, Emory University
Committee Members	Dr. Arri Eisen, Emory University Dr. Peng Jin, Emory University

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