The Epigenetic and Epitranscriptomic Regulation of Immune Activation
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».