The Epigenetic and Epitranscriptomic Regulation of Immune Activation

Abstract

Gene expression in immune cells is regulated by intricate mechanisms that contribute to the immune response. Precise control of this expression is crucial for achieving well-timed and finely tuned expression of genes and pathways associated with inflammation. Disruption of this delicate balance can lead to severe complications, such as infections, auto-inflammatory disorders, or autoimmune diseases. This thesis elucidates the role of histone regulation and post-transcriptional regulation via m6A modification in both the adaptive and innate immune systems. Chapter 1 provides a general introduction, setting the stage for the detailed investigations that follow. Chapter 2 delves into the impact of histone regulation on CD4+ T cell activation by inhibiting key co-activators and HAT proteins P300/CBP. The potential of targeted inhibition of P300/CBP through BET inhibition is explored as a therapeutic approach for treating Juvenile Idiopathic Arthritis (JIA). In Chapter 3, the focus shifts to the role of m6A modification in monocyte activation. Following monocyte activation, differential expression of multiple m6A-associated proteins is uncovered, leading to elevated m6A levels. m6A methylation is identified on numerous genes within the TNF signaling via the NFkB pathway, including TNF itself. The m6A reader YTHDC1 binds to m6A-modified TNF, promoting TNF protein expression by facilitating the nuclear export of TNF mRNA. Chapter 4 elaborates on the increased expression of WTAP observed in monocyte activation. An alternative WTAP promoter is identified, which increases expression of a specific WTAP mRNA isoform in monocyte activation under the regulation of NFkB. Chapter 5 returns to JIA, demonstrating expression differences of m6A-associated proteins and increased m6A levels in monocytes derived from the inflamed joint of JIA patients. Decreased expression of the m6A eraser FTO can be induced by environmental cues from the synovial fluid of the inflamed joint. Chapter 6 examines the role of m6A in host immunity against Respiratory Syncytial Virus (RSV) infection. m6A modifications are detected on respiratory viruses, including RSV, which enhances viral replication and immune evasion. On host transcripts, the m6A reader YTHDC1 negatively regulates RSV entry by reducing the expression of the RSV entry receptor CX3CR1. The role of m6A in adaptive immunity and CD4+ T cell activation is discussed in Chapter 7 and Chapter 8, particularly in regulating stability of CD40L and TNF mRNA via m6A reader protein YTHDF2. Chapter 9 provides a general discussion, summarizing the findings of the thesis. Both histone regulation and m6A modification emerge as critical mechanisms for precisely modulating gene expression in different components of the immune system. This chapter explores the intricate interplay between these mechanisms, highlighting factors such as timing, transcript specificity, and reader specificity for m6A modifications. Furthermore, the potential implications of BET inhibition and m6A protein inhibition are underscored as promising therapeutic strategies for addressing autoimmune diseases. Overall, this thesis provides novel insights into how distinct forms of gene regulation orchestrate the immune response. Epigenetic and epitranscriptomic mechanisms, such as histone regulation and m6A modifications, exhibit multifaceted roles in T cell and monocyte activation.