Dynamic Change in the Stochiometry of ETO2 and SCL Governs the Transition to Terminal Differentiation in Erythroid Progenitors.
Notice bibliographique
Résumé
Abstract As highly proliferative erythroid progenitors commit to terminal differentiation, they also progressively undergo growth arrest. To determine the mechanisms underlying the appropriate timing of erythroid gene expression and those associated with growth cessation, we analyzed the dynamical composition of the multiprotein complex nucleated by the bHLH transcription factor SCL, a crucial regulator of erythropoiesis that absolutely requires interaction with other factors to activate transcription. In progenitor cells, the SCL complex marks a subset of erythroid specific genes (alpha-globin, P4.2, glycophorin A) that are transcribed later in differentiating cells, conducting cells toward terminal maturation. To unravel the regulation of transcription by SCL, we used tagging/proteomics approaches in two differentiation-inducible erythroid cell lines, coupled with binding assays to immobilized DNA templates and chromatin immunoprecipitation. Our analyses reveal that the core complex comprised of known proteins (SCL, GATA-1, LMO2, Ldb1 and E2A) and two additional E protein family members, HEB and E2-2, did not change with differentiation. Strikingly, this complex recruits HDAC1-2 in undifferentiated cells which were exchanged with TRRAP, a chromatin remodelling factor, upon differentiation, suggesting an epigenetic regulation of erythroid differentiation mediated by the core SCL complex. Finally, we identified the corepressor ETO2 targeted via this complex through direct interaction with E2A/HEB. In vivo, ETO2 represses the transcription of SCL target genes both in transient assays and in chromatin. During erythroid differentiation, ETO2 remains associated with the SCL complex bound to erythroid promoters. However, the stoichiometry of ETO2 and SCL/HEB changes as SCL and HEB levels increase with erythroid differentiation, both in nuclear extracts and on DNA. To determine the functional consequence of this imbalance in activator to co-repressor ratio, we delivered ETO2 siRNA in primary hematopoietic cells and found an accelerated onset of SCL target genes on induction of erythroid differentiation, and conversely, these genes were decreased following ectopic ETO2 expression. Strikingly, inhibition of ETO2 expression in erythroid progenitors arrests cell proliferation, indicating that ETO2 is required for their expansion. We therefore analyzed gene expression in purified erythroid progenitors and differentiating erythroid cells (E1-E5) and found an inverse correlation between the mRNA levels of ETO2 and cyclin-dependent kinase inhibitors. Moreover, ETO2 siRNA treatment of primary erythroid progenitors results in increased p21 CDKI and Gfi1b expression, as assessed by real-time PCR. Finally, we show by chromatin immunoprecipitation that Gfi-1b, p21 and p27, are direct targets of the SCL- ETO2 complex. We therefore conclude that ETO2 regulates the erythroid lineage fate by repressing SCL marked erythroid genes in undifferentiated cells, and by controlling the expansion of erythroid progenitors. Our study elucidates the dual function of ETO2 in the erythroid lineage and sheds light on epigenetic mechanisms coordinating red blood cell proliferation and differentiation.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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) | 0,000 | 0,000 |
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 tête enseignante, 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 ».