The role of ubiquitin carboxyl-terminal hydrolase isozyme L1/UCHL1 in human lung diseases: environmental exposure, epigenetics and epigenetic editing

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    Environmental exposure to cigarette smoke or toxic metal cadmium is closely associated with various airway diseases, including lung cancer and chronic lung diseases. Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) is a member of the ubiquitin-proteasome system and involved in protein turnover, and its dysregulation has been associated with airway diseases.
    The thesis first examines the molecular mechanisms of chronic cadmium-induced adaptation and carcinogenesis. In this part, epiproteome (proteomic analysis of histone marks) and subproteome (proteomic analysis of subcellular proteins) approaches were used to interrogate cadmium-transformed human bronchial epithelial cells, and we found that these cadmium-adapted cells exhibit epithelial-mesenchymal transition (EMT) and enhanced cell migration. Through subproteome profiling, we found that UCHL1 was the top downregulated protein upon chronic cadmium exposure and its lower expression was closely associated with EMT.
    In the second part of the thesis, we continued to explore the role of UCHL1 in smoking-related disease through transcription modulation of UCHL1 in different lung cell lines. We first confirmed that UCHL1 was highly expressed in current smokers. As UCHL1 plays a crucial role in EMT and fibrosis, we further checked whether UCHL1 also functions on extra cellular matrix (ECM) production and airway remodeling. We increased the expression of UCHL1 by a CRISPR/dCas9-based artificial transcription activator and demonstrated a subsequent increase in the expression of the ECM gene COL1A1. Downregulation of UCHL1 was obtained via writing of the repressive histone mark H3K27 methylation and indirectly resulted in a decreased expression of ECM genes COL1A1 and fibronectin. Overall, these results suggest that UCHL1 is a mediator in the synthesis of ECM proteins and may be involved in smoking-induced airway remodeling.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    Begeleider(s)/adviseur
    • Rots, Marianne, Supervisor
    • Hylkema, Machteld, Supervisor
    • Lau, Andy T Y, Supervisor, Externe Persoon
    • Xu, Y.-M., Supervisor, Externe Persoon
    Datum van toekenning14-sep-2021
    Plaats van publicatie[Groningen]
    Uitgever
    DOI's
    StatusPublished - 2021

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