Investigating the role of RNA-editing in the human hearts with dilated cardiomyopathy at single-cell type resolution
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Author(s)
Hassani, Mohamed
Type
Thesis
Abstract
RNA editing dysregulation has been linked to various cardiac diseases. In this study we have explored the role of RNA editing in dilated cardiomyopathy (DCM) using single-cell transcriptomics to profile RNA editing events in different cell types of the human heart.
Cardiomyopathy is a disease that affects the heart muscle and can lead to heart failure or other complications. One type of Cardiomyopathy is Dilated Cardiomyopathy (DCM). In DCM the heart muscle becomes stretched and thin, causing the heart to become enlarged. Thereafter, the weakened heart muscle is unable to pump blood effectively, thus leading to heart failure. This can be due to inherited genetic factors and / or epigenetic (gene regulation) factors.
Our data analysis revealed a significant correlation between RNA editing dysregulation, histone protein post-translational modifications (PTMs), and chromatin reorganisation in DCM heart muscle cells. Consequently, we have identified gene transcription regulation impacting nucleic acid metabolism pathways, as well as downstream impairment of cardiac muscle motility. Furthermore, our results also demonstrate a strong correlation between RNA editing dysregulation and non-histone protein PTMs, highlighting their impact on the cytoskeleton (including microfilaments, intermediate filaments, and microtubules), which, in turn, affects organelle dynamics and cell motility.
Significantly, we have found cardiomyocytes to be the most RNA-edited cells in the heart, with ADAR enzymes being the main RNA editors. This discovery underscores a significant correlation between RNA editing dysregulation, nucleic acid metabolism, ubiquitination, and cellular motility.
Exploring aberrant RNA editing may provide a deeper understanding of the underlying mechanisms that alter gene expression and RNA regulation in DCM. This insight holds promise as an early biomarker, enabling the detection of DCM prior to the manifestation of clinical symptoms. Moreover, by reprogramming RNA editing enzymes, it may be possible to restore healthy metabolism and motility.
Cardiomyopathy is a disease that affects the heart muscle and can lead to heart failure or other complications. One type of Cardiomyopathy is Dilated Cardiomyopathy (DCM). In DCM the heart muscle becomes stretched and thin, causing the heart to become enlarged. Thereafter, the weakened heart muscle is unable to pump blood effectively, thus leading to heart failure. This can be due to inherited genetic factors and / or epigenetic (gene regulation) factors.
Our data analysis revealed a significant correlation between RNA editing dysregulation, histone protein post-translational modifications (PTMs), and chromatin reorganisation in DCM heart muscle cells. Consequently, we have identified gene transcription regulation impacting nucleic acid metabolism pathways, as well as downstream impairment of cardiac muscle motility. Furthermore, our results also demonstrate a strong correlation between RNA editing dysregulation and non-histone protein PTMs, highlighting their impact on the cytoskeleton (including microfilaments, intermediate filaments, and microtubules), which, in turn, affects organelle dynamics and cell motility.
Significantly, we have found cardiomyocytes to be the most RNA-edited cells in the heart, with ADAR enzymes being the main RNA editors. This discovery underscores a significant correlation between RNA editing dysregulation, nucleic acid metabolism, ubiquitination, and cellular motility.
Exploring aberrant RNA editing may provide a deeper understanding of the underlying mechanisms that alter gene expression and RNA regulation in DCM. This insight holds promise as an early biomarker, enabling the detection of DCM prior to the manifestation of clinical symptoms. Moreover, by reprogramming RNA editing enzymes, it may be possible to restore healthy metabolism and motility.
Version
Open Access
Date Issued
2023-05-05
Date Awarded
01/03/2024
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Srivastava, Prashant
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Master of Philosophy (MPhil)