Retrotransposons in chronic pain: focusing on roles in gene regulation and neuroinflammation



Price, Emma ORCID: 0000-0002-7538-7831
(2020) Retrotransposons in chronic pain: focusing on roles in gene regulation and neuroinflammation. PhD thesis, University of Liverpool.

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Abstract

Pain has evolved as a protective mechanism to signal danger, threat, injury and inflammation to an organism; however, this becomes problematic and detrimental to human physiological and psychological wellbeing when it persists without a noxious cause. Transposable elements (TEs) are functional components of genomes that contribute to species specific gene expression patterns; therefore, we explored the role of TEs in the context of pain gene expression. This work focuses on non-LTR retrotransposons as they remain the major active class of autonomous TEs in the human genome. We first present a study using CRISPR that demonstrates the effect of a human specific retrotransposon SINE-VNTR-Alu (SVA) insertion as a contributor to human specific gene regulation at the locus encoding pain genes TRPV1 and TRPV3. We also show that the SVA at TRPV1 and TRPV3 has regulatory properties and further demonstrate its polymorphic nature and highlight potential links to pain phenotypes. Recent work has also identified that expression of the retrotransposon LINE-1 (L1) is a pathogenic contributor to neurodegenerative disease in the central nervous system and an inducer of inflammation in non-pathological ageing. Chronic pain is an age associated disorder and is driven by the onset of neuroinflammation in the peripheral nervous system. To assess whether L1 expression contributes to this mechanism associated with chronic pain, we present another proof of principle experiment in which we demonstrate increased L1 expression in ageing DRG. Furthermore, we explored L1 expression in response to a novel anti-inflammatory drug and found unexpected increases in expression. The data from this study implies a strong case for further investigation and a potential role for L1 in neuroinflammation in the peripheral nervous system. To summarise, the work presented in this thesis describes the first studies to investigate the role of retrotransposons in several contexts that may contribute to the development of chronic pain and modulation of pain phenotype.

Item Type: Thesis (PhD)
Uncontrolled Keywords: Transposons, Pain, Gene regulation, Inflammation
Divisions: Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences > School of Medicine
Depositing User: Symplectic Admin
Date Deposited: 13 Aug 2020 15:14
Last Modified: 19 Jan 2023 00:00
DOI: 10.17638/03076769
Supervisors:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3076769