In her PhD research, Ellen van Vroonhoven (UMC Utrecht) identified novel functions of post-transcriptional RNA modification of N6-methyladenosine (m6A) and its regulatory proteins in both innate- and adaptive immune cells. For example, she found evidence that CD4+ T cell activation is mediated by m6A. Also, she demonstrated that m6A modifications modulate TNF expression in both CD4+ T lymphocytes and monocytes. These m6A modifications are thought to be involved in anti-viral immune responses against RSV infection and in Juvenile Idiopathic Arthritis (JIA) pathogenesis.
Gene expression is regulated at different levels. The rate of gene transcription, genomic stability and expression of noncoding sequences can be regulated by modifications on both DNA bases and histones. In addition, regulation of expression also occurs at the RNA transcript level. Post-transcriptional regulation involving RNA binding proteins and modifications, can determine the turnover and translation rate of messenger RNA transcripts. Post-transcriptional regulation has been demonstrated to modulate the expression of proteins involved in T cell function such as cytokines (for example, tumor necrosis factor (TNF)) and cell surface receptors. N6-methyladenosine (m6A) is the most abundant and well-studied RNA modification in eukaryotic cells. This modification is known to be involved in the regulation of various molecular mechanisms including immune cell differentiation and function, autoimmune disease pathogenesis and anti-viral immunity. The work described in the PhD thesis of Ellen van Vroonhoven, MSc (Center for Translational Immunology, UMC Utrecht) is aimed to create more insight into the role of m6A and its regulatory proteins in innate- and adaptive immune cell function, anti-viral immunity against respiratory syncytial virus (RSV) and juvenile idiopathic arthritis (JIA) pathogenesis.
Dr. Ellen van Vroonhoven
Novel functions of RNA modifications
In her thesis, Ellen van Vroonhoven identified novel functions of this RNA modification and its regulatory proteins in both innate- and adaptive immune cells. She found evidence that CD4+ T cell activation is mediated by m6A. Also, she demonstrated that m6A modifications modulate TNF expression in both CD4+ T lymphocytes and monocytes. Finally, in further experimental studies Ellen described how m6A is involved in anti-viral immune responses against RSV infection.
Pathogenesis of JIA
In another experiment, Ellen and co-workers observed reduced expression of FTO (an enzyme involved in the removal of m6A) and increased m6A levels in monocytes from JIA patients, indicating a potential influence on the microenvironment of synovial joints. Additionally, exposing monocytes to synovial fluid from JIA patients led to decreased FTO expression. The deletion of FTO in monocytes led to a decrease in their activation, underscoring the pivotal roles of FTO and m6A in JIA pathophysiology. These findings suggest that FTO expression could serve as a biomarker for JIA and position FTO as a potential target for treating JIA and potentially also other autoimmune disorders in the future.
“Altogether, the studies described in my PhD thesis provide novel insight in the role of m6A modifications and its regulatory proteins in the function of various processes of the innate- and adaptive immune system. The findings also indicate that targeting m6A regulatory proteins might be of interest for the treatment of autoimmune diseases and viral infections.”
PhD defense
Ellen van Vroonhoven, MSc (1992, Eindhoven) defended her PhD thesis on February 4, 2025 at Utrecht University. The title of her thesis was “Epitranscriptomic regulation in immunity and autoimmune disease – Unraveling novel implications of RNA modification m6A”. Supervisors were Jorg van Loosdregt, PhD (Center for Translational Immunology, UMC Utrecht) and Bas Vastert, MD PhD (Center for Translational Immunology and Department of Rheumatology and Clinical immunology, UMC Utrecht). On the 1st of July, 2023 Ellen started as a senior research associate at the department of Translational Medicine at Genmab (Utrecht).
