RESUMO
The hematopoietic system declines with age. Myeloid-biased differentiation and increased incidence of myeloid malignancies feature aging of hematopoietic stem cells (HSCs), but the mechanisms involved remain uncertain. Here, we report that 4-mo-old mice deleted for transcription intermediary factor 1γ (Tif1γ) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1γ is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1γ controls TGF-ß1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1γ(-/-) and old HSCs are more sensitive to TGF-ß signaling. Importantly, we identified two populations of HSCs specifically discriminated by Tgfbr1 expression level and provided evidence of the capture of myeloid-biased (Tgfbr1(hi)) and myeloid-lymphoid-balanced (Tgfbr1(lo)) HSCs. In conclusion, our data provide a new paradigm for Tif1γ in regulating the balance between lymphoid- and myeloid-derived HSCs through TGF-ß signaling, leading to HSC aging.
Assuntos
Senescência Celular , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fatores de Transcrição/metabolismo , Envelhecimento/metabolismo , Animais , Antígenos CD/metabolismo , Separação Celular , Senescência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Camundongos , Células Mieloides/metabolismo , Fenótipo , Poliubiquitina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta1/farmacologia , Ubiquitinação/efeitos dos fármacosRESUMO
The differentiation of human peripheral blood monocytes into macrophages can be reproduced ex vivo by culturing the cells in the presence of colony-stimulating factor 1 (CSF1). Using microarray profiling to explore the role of microRNAs (miRNAs), we identified a dramatic decrease in the expression of the hematopoietic specific miR-142-3p. Up- and down-regulation of this miRNA in primary human monocytes altered CSF1-induced differentiation of monocytes, as demonstrated by changes in the expression of the cell surface markers CD16 and CD163. One of the genes whose expression is repressed by miR-142-3p encodes the transcription factor Early Growth Response 2 (Egr2). In turn, Egr2 associated with its co-repressor NGFI-A (Nerve Growth Factor-Induced gene-A) binding protein 2 (NAB2) binds to the pre-miR-142-3p promoter to negatively regulate its expression. Interestingly, the expression of miR-142-3p is abnormally low in monocytes from patients with the most proliferative forms of chronic myelomonocytic leukemia (CMML), and miR-142-3p re-expression in CMML dysplastic monocytes can improve their differentiation potential. Altogether, miR-142-3p which functions in a molecular circuitry with Egr2 is an actor of CSF1-induced differentiation of human monocytes whose expression could be altered in CMML.
Assuntos
Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , MicroRNAs/genética , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Células K562 , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/patologia , Macrófagos/citologia , Macrófagos/metabolismo , MicroRNAs/biossíntese , MicroRNAs/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
MOZ and MLL encoding a histone acetyltransferase and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. We have previously shown that MOZ and MLL cooperate to activate HOXA9 gene expression in hematopoietic stem/progenitors cells. To dissect the mechanism of action of this complex, we decided to identify new proteins interacting with MOZ. We found that the scaffold protein Symplekin that supports the assembly of polyadenylation machinery was identified by mass spectrometry. Symplekin interacts and co-localizes with both MOZ and MLL in immature hematopoietic cells. Its inhibition leads to a decrease of the HOXA9 protein level but not of Hoxa9 mRNA and to an over-recruitment of MOZ and MLL onto the HOXA9 promoter. Altogether, our results highlight the role of Symplekin in transcription repression involving a regulatory network between MOZ, MLL and Symplekin.
Assuntos
Sistema Hematopoético/citologia , Histona Acetiltransferases/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Linhagem Celular , Histona-Lisina N-Metiltransferase , Proteínas de Homeodomínio/genética , Humanos , Poliadenilação , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Trim33/Tif1γ (Trim33) is a member of the tripartite motif family. Using a conditional hematopoietic-specific Trim33 knock-out (Trim33(Δ/Δ)) mouse, we showed previously that Trim33 deficiency in hematopoietic stem cells leads to severe defects in hematopoiesis, resembling the main features of human chronic myelomonocytic leukemia. We also demonstrated that Trim33 is involved in hematopoietic aging through TGFß signaling. Nevertheless, how Trim33 contributes to the terminal stages of myeloid differentiation remains to be clarified. We reveal here the crucial role of Trim33 expression in the control of mature granulomonocytic differentiation. An important component of Trim33-deficient mice is the alteration of myeloid differentiation, as characterized by dysplastic features, abnormal granulocyte and monocyte maturation, and the expansion of CD11b(+)Ly6G(high)Ly6C(low) myeloid cells, which share some features with polymorphonuclear-myeloid-derived suppressor cells. Moreover, in Trim33(Δ/Δ) mice, we observed the alteration of CSF-1-mediated macrophage differentiation in association with the lack of Csf-1 receptor. Altogether, these results indicate that Trim33 deficiency leads to the expansion of a subset of myeloid cells characterizing the myelodysplastic/myeloproliferative neoplasm.