RESUMO
Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.
Assuntos
Células-Tronco Hematopoéticas , Ribonucleoproteínas Nucleares Heterogêneas , Proteostase , Animais , Camundongos , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Camundongos Knockout , Proteostase/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.
Assuntos
Linfócitos B , Transformação Celular Neoplásica , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias , Animais , Humanos , Camundongos , Afinidade de Anticorpos/genética , Linfócitos B/patologia , Centro Germinativo , Mutação , Proteínas de Neoplasias/genética , Linfoma Difuso de Grandes Células B/genética , Transformação Celular Neoplásica/genética , Seleção GenéticaRESUMO
RNA binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be found dysregulated in hematological malignancies. Here, we identify the RBP RBMX and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX/L1 are overexpressed in acute myeloid leukemia (AML) primary patients compared to healthy individuals, and RBMX/L1 loss delayed leukemia development. RBMX/L1 loss lead to significant changes in chromatin accessibility, as well as chromosomal breaks and gaps. We found that RBMX/L1 directly bind to mRNAs, affect transcription of multiple loci, including CBX5 (HP1α), and control the nascent transcription of the CBX5 locus. Forced CBX5 expression rescued the RBMX/L1 depletion effects on cell growth and apoptosis. Overall, we determine that RBMX/L1 control leukemia cell survival by regulating chromatin state through their downstream target CBX5. These findings identify a mechanism for RBPs directly promoting transcription and suggest RBMX/L1, as well as CBX5, as potential therapeutic targets in myeloid malignancies.
Assuntos
Cromatina , Leucemia Mieloide Aguda , Animais , Cromatina/genética , Regulação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genéticaRESUMO
The cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors. Additionally, we discover a significant increase in RNA binding activity of MSI2 in leukemic stem cells compared with normal hematopoietic stem and progenitor cells, resulting in selective regulation of MSI2's oncogenic targets. This provides a basis for MSI2 increased dependency in leukemia cells compared to normal cells. Moreover, our study provides a way to measure RBP function in rare cells and suggests that RBPs can achieve differential binding activity during cell state transition independent of gene expression.
Assuntos
Diferenciação Celular/genética , Células-Tronco Hematopoéticas/patologia , Leucemia/genética , Células-Tronco Neoplásicas/patologia , Proteínas de Ligação a RNA/metabolismo , Adenosina Desaminase/genética , Animais , Sítios de Ligação/genética , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Humanos , Leucemia/sangue , Leucemia/patologia , Camundongos , Camundongos Knockout , Cultura Primária de Células , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , RNA-Seq , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
In many years, the nickel electroplating technique has been applied to coat nickel on other materials for their increased properties. Nickel electroplating has played a vital role in our modern society but also caused considerable environmental concerns due to the mass discharge of its wastewater (i.e. containing nickel and other heavy metals) to the environment. Thus, there is a growing need for treating nickel electroplating wastewater to protect the environment and, in tandem, recover nickel for beneficial use. This study explores a novel application of membrane distillation (MD) for the treatment of nickel electroplating wastewater for a dual purpose: facilitating the nickel recovery and obtaining fresh water. The experimental results demonstrate the technical capability of MD to pre-concentrate nickel in the wastewater (i.e. hence pave the way for subsequent nickel recovery via chemical precipitation or electrodeposition) and extract fresh water. At a low operating feed temperature of 60 °C, the MD process increased the nickel content in the wastewater by more than 100-fold from 0.31 to 33 g/L with only a 20% reduction in the process water flux and obtained pure fresh water. At such high concentration factors, the membrane surface was slightly fouled by inorganic precipitates; however, membrane pore wetting was not evident, confirmed by the purity of the obtained fresh water. The fouled membrane was effectively cleaned using a 3% HCl solution to restore its surface morphology. Finally, the preliminary thermal energy analysis of the combined MD-chemical precipitation/electrodeposition process reveals a considerable reduction in energy consumption of the nickel recovery process.
