Tif1gamma Is Essential for Macrophage Differentiation
Notice bibliographique
Résumé
Abstract Abstract 2370 TIF1gamma (or TRIM33) is an ubiquitous nuclear protein that belongs to the transcriptional intermediary factor 1 family. Human and mouse TIF1gamma are closely related to zebrafish moonshine (mon), a gene whose mutations disrupt embryonic and adult hematopoiesis with severe red blood cell aplasia. Targeted deletion of Tif1gamma is embryonic lethal in mice. In zebrafish and human CD34+ cells, TIF1gamma functionally links positive elongation factors such as p-TEFb and FACT to blood specific transcription complexes (e.g. the SCL/TAL1 complex) to regulate elongation of genes by antagonizing Pol II pausing. TIF1gamma also affects the human hematopoietic progenitor cell response to the cytokines of the transforming growth factor-beta superfamily through various mechanisms. Recently, we showed that the loss of Tif1gamma in mouse hematopoietic stem cells (cFES-Cre-Tif1gamma) favors the expansion of the granulo-monocytic progenitor compartment. The gene deletion induces the age-dependent appearance of a cell-autonomous myeloproliferative disorder with myelodysplastic features, monocytosis, and hepatosplenomegaly that recapitulates essential features of human chronic myelomonocytic leukemia (CMML). Interestingly, TIF1gamma is almost undetectable in leukemic cells of 35% of patients with CMML. This down-regulation is related to the hyper-methylation of CpG sequences in the gene promoter. Our results demonstrated that TIF1gamma is an epigenetically regulated tumor suppressor gene in hematopoietic cells. In addition, an altered production of peritoneal macrophages was observed in our mouse model. These macrophages did not adhere to the plastic and were morphologically abnormal in vitro. In bone marrow and in Lin- progenitor cells, Tif1gamma deletion leads to a significant decrease of cfms (Csf-1r) expression, required for the differentiation, proliferation, and survival of monocytic phagocytes. We also identified in CMML patients the association between low levels of TIF1gamma and cFMS (Aucagne et al., J. Clin. Invest., 121, 2361–2370, 2011). To gain insight into the possible mechanism accounting for diminished accumulation of macrophages, we examined the expression of c-Fms. We show that level of its expression is reduced significantly in blood monocytes isolated from Tif1gamma-deleted mice. When Tif1gamma-deleted sorted myeloid cells were induced to differentiate into macrophages in presence of CSF-1, a delayed production of few abnormal large macrophages was observed. Apoptosis was associated with this alteration of differentiation. This phenomenon was also characterized in young mice not developing the disease yet. The morphological abnormalities were correlated with very important alterations of specific macrophage differentiation markers. Expression of specific transcription factors involved in macrophage differentiation was deeply deregulated. Moreover, macrophage function such as migration, cytokine or chemokine secretion in response to LPS was altered. Likewise, in vitro differentiation of monocytes into dendritic cells was also abnormal. Altogether, our results suggest that monocyte plasticity is at least partially orchestrated by Tif1gamma. Disclosures: No relevant conflicts of interest to declare.
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 | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».