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.
N
-methyladenosine (m
A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m
A ...modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m
A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m
A coupled with ribosome profiling reveals that m
A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.
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.
ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n. ATRX mutations are found in nearly all tumours that maintain their telomeres ...via the alternative lengthening of telomere (ALT) pathway, and ATRX is known to suppress this pathway. Here, we show that recruitment of ATRX to telomeric repeats depends on repeat number, orientation and, critically, on repeat transcription. Importantly, the transcribed telomeric repeats form RNA–DNA hybrids (R‐loops) whose abundance correlates with the recruitment of ATRX. Here, we show loss of ATRX is also associated with increased R‐loop formation. Our data suggest that the presence of ATRX at telomeres may have a central role in suppressing deleterious DNA secondary structures that form at transcribed telomeric repeats, and this may account for the increased DNA damage, stalling of replication and homology‐directed repair previously observed upon loss of ATRX function.
Synopsis
This study shows that ATRX recruitment to G‐rich tandem repeats depends on repeat transcription, length and orientation and is associated with R‐loops. ATRX loss increases R‐loops at these sites suggesting that ATRX resolves DNA secondary structures.
Recruitment of ATRX at G‐rich tandem repeats depends on transcription and is associated with the presence of R‐loops.
ATRX recruitment depends on the non‐template strand being G‐rich suggesting the presence of G quadruplex DNA.
R‐loops at these sites increase in the absence of ATRX.
This study shows that ATRX recruitment to G‐rich tandem repeats depends on repeat transcription, length and orientation and is associated with R‐loops. ATRX loss increases R‐loops at these sites suggesting that ATRX resolves DNA secondary structures.
Abstract
In the new general school curriculum, the Natural Science subject is taught in an integrated way according to the STEM-oriented education. However, it is not simple to build a topic of ...teaching Natural Science subject towards STEM standards. In this context, Hacking STEM is one of the ideal solutions to solve the aforementioned problem. The paper focuses on analyzing what Hacking STEM is, the advantages and disadvantages of Microsoft Hacking STEM when applied in Vietnam, the process of using Microsoft Hacking STEM projects, analyzing a specific project, the relationship between these projects with the Natural Science subject in the new general school curriculum and with the subjects of Natural Sciences being taught in the current period.
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
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.
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.
The aim of the present study was to evaluate the effects of nutritional interventions in patients with hypopharyngeal-laryngeal and esophageal cancers treated with radiotherapy. Patients who received ...clinical intervention were compared with a control group. The intervention group received active nutritional support according to the regimen developed by the study team, while the control group followed a normal diet at the hospital or at home. After 1 month, in the intervention group, the patients' weight increased by 0.5+ or -1.7 kg, while in the control group, the patients weight decreased by 1.6+ or -1.9 kg. In addition, body mass index in the intervention group increased by 0.2+ or -0.6 kg/m.sup.2, whereas this decreased by 0.6+ or -0.7 kg/m.sup.2 in the control group. Significant differences between the groups were observed for both parameters (P<0.001). As regards the quality of life, the general symptoms of the patients in the intervention group improved (a decrease of 3.4+ or -11.9 points), while those in the control group tended to worsen (an increase of 5.5+ or -12.6 points). Specifically, fatigue, and vomiting and nausea decreased by 2.4+ or -18.0 and 73+ or -23.9 points in the intervention group, respectively, whereas these increased by 8.0+ or -16.5 and 9.9+ or -26.4 points, respectively in the control group, with differences between groups being statistically significant for both parameters (P<0.05). On the whole, the present study demonstrates that for patients with hypopharyngeal-laryngeal and esophageal cancers who are at a high risk of developing malnutrition, active nutritional interventions during radiotherapy improve the nutritional status and, ultimately, the quality of life of the patients. Key words: nutritional intervention, quality of life, hypopharyngeal-laryngeal cancer, esophageal cancers
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
(HP1α), and control the nascent transcription of the
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
. 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.
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