METTL3 regulates WTAP protein homeostasis

The Wilms tumor 1 (WT1)-associated protein (WTAP) is upregulated in many tumors, including, acute myeloid leukemia (AML), where it plays an oncogenic role by interacting with different proteins involved in RNA processing and cell proliferation. In addition, WTAP is also a regulator of the nuclear complex required for the deposition of N6-methyladenosine (m6A) into mRNAs, containing the METTL3 methyltransferase. However, it is not clear if WTAP may have m6A-independent regulatory functions that might contribute to its oncogenic role. Here, we show that both knockdown and overexpression of METTL3 protein results in WTAP protein upregulation, indicating that METTL3 levels are critical for WTAP protein homeostasis. However, we show that WTAP upregulation is not sufficient to promote cell proliferation in the absence of a functional METTL3. Therein, these data indicate that the reported oncogenic function of WTAP is strictly connected to a functional m6A methylation complex

Decoding Algorithms and HW Strategies to Mitigate Uncertainties in a PCM-Based Analog Encoder for Compressed Sensing

Analog In-Memory computing (AIMC) is a novel paradigm looking for solutions to prevent the unnecessary transfer of data by distributing computation within memory elements. One such operation is matrix-vector multiplication (MVM), a workhorse of many fields ranging from linear regression to Deep Learning. The same concept can be readily applied to the encoding stage in Compressed Sensing (CS) systems, where an MVM operation maps input signals into compressed measurements. With a focus on an encoder built on top of a Phase-Change Memory (PCM) AIMC platform, the effects of device non-idealities, namely programming spread and drift over time, are observed in terms of the reconstruction quality obtained for synthetic signals, sparse in the Discrete Cosine Transform (DCT) domain. PCM devices are simulated using statistical models summarizing the properties experimentally observed in an AIMC prototype, designed in a 90 nm STMicroelectronics technology. Different families of decoders are tested, and tradeoffs in terms of encoding energy are analyzed. Furthermore, the benefits of a hardware drift compensation strategy are also observed, highlighting its necessity to prevent the need for a complete reprogramming of the entire analog array. The results show >30 dB average reconstruction quality for mid-range conductances and a suitably selected decoder right after programming. Additionally, the hardware drift compensation strategy enables robust performance even when different drift conditions are tested

A positive feed-forward regulatory loop between METTL3 and WTAP sustains the oncogenic role of the m6A methylation complex in myeloid leukemia

The Wilms tumor 1 (WT1)-associated protein (WTAP) is upregulated in many tumours, including, acute myeloid leukemia (AML), where it plays an oncogenic role by interacting with different proteins involved in RNA processing and cell proliferation. In addition, WTAP is also a regulator of the nuclear complex required for the deposition of N6-Methyladenosine (m6A) into mRNAs, containing the METTL3 methyltransferase. However, it is not clear if WTAP may have m6A-independent regulatory functions that might contribute to its oncogenic role. Here, we show that both knockdown and overexpression of METTL3 protein results in WTAP protein upregulation, indicating that METTL3 levels are critical for WTAP protein homeostasis. However, we show that WTAP upregulation is not sufficient to promote cell proliferation in the absence of a functional METTL3. Our results indicate the existence of a positive feedforward regulatory loop, where METTL3 upregulates WTAP, which is relevant to increase WTAP expression concomitantly to the METTL3/METTL14 core m6A methylation complex and sustain the oncogenic role reported for the m6A modification complex in leukemia

nAChRs gene expression and neuroinfammation inAPPswe/PS1dE9 transgenic mouse

An evaluation of the APPswe/PS1dE9 transgenic AD mouse, presenting with the toxic Aβ1-42 deposition found in human AD, allowed us to characterize time-dependent changes in inflammatory and cholinergic markers present in AD. Astrogliosis was observed in cortex and hippocampus, with cellular loss occurring in the same areas in which Aβ plaques were present. In this setting, we found early significantly elevated levels of IL-1β and TNFα gene expression; with the hippocampus showing the highest IL-1β expression. To investigate the cholinergic anti-inflammatory pathway, the expression of nicotinic receptors (nAChRs) and cholinesterase enzymes also was evaluated. The anti-inflammatory nAChRα7, α4, and β2 were particularly increased at 6 months of age in the hippocampus, potentially as a strategy to counteract Aβ deposition and the ensuing inflammatory state. A time-dependent subunit switch to the α3β4 type occurred. Whether α3, β4 subunits have a pro-inflammatory or an inhibitory effect on ACh stimulation remains speculative. Aβ1-42 deposition, neuronal loss and increased astrocytes were detected, and a time-dependent change in components of the cholinergic anti-inflammatory pathway were observed. A greater understanding of time-dependent Aβ/nAChRs interactions may aid in defining new therapeutic strategies and novel molecular targets

Cholinergic Markers and Cytokines in OSA Patients

The role of inflammation and dysfunction of the cholinergic system in obstructive sleep apnea (OSA) has not exhaustively clarified. Thus, in this study, we explore the non-neuronal cholinergic system and the balance of T helper (Th) 17- and T regulatory (Treg)-related cytokines in OSA patients. The study includes 33 subjects with obstructive sleep apnea and 10 healthy controls (HC). The expression levels of cholinergic system component, RAR-related orphan receptor (RORc), transcription factor forkhead box protein 3 (Foxp3) and cytokines were evaluated. Th17- and Treg-related cytokines, choline levels and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activity were quantified in OSA and control subjects. AChE and nicotinic receptor α 7 subunit (α7nAChR) gene expression and serum levels of choline, AChE and BuChE were lower in OSA patients than in the HC group. Compared with the HC group, OSA patients exhibited an increased expression, secretion and serum levels of pro-inflammatory cytokines, a reduced expression, secretion and serum levels of transforming growth factor (TGF)β and reduced Foxp3 mRNA levels. The Th17/Treg-related cytokine ratio was higher in the OSA group. Our results confirm and reinforce the hypothesis that OSA may be considered a systemic inflammatory disease, and that an imbalance of non-neuronal cholinergic and pro/anti-inflammatory cytokines may contribute to development and progression of comorbidities in OSA subjects. The evaluation of Th17/Treg-related cytokine may provide an additional explanation for OSA pathogenesis and clinical features, opening new directions for the OSA management

The METTL3/METTL14 m6A methylation complex plays a crucial role in Chronic Myeloid Leukemia survival by regulating MYC expression.

Chronic Myeloid Leukemia (CML) is a malignant myeloproliferative disease caused by a chromosomal translocation that produces the constitutively activated tyrosine kinase BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge for curing CML patients. To gain insight into the role of m6A modification in CML, we analyze the role of the METTL3/METTL14 m6A writing complex in the BCR-ABL1+ K562 CML cellular model. We show that knockdown of METTL3 and METTL14 strongly impaired proliferation of both TKI-sensitive and TKI-resistant cells. Furthermore, we demonstrate that MYC oncogenes is highly m6A methylated in CML and that m6A marks are required for its efficient expression. Therefore, our findings demonstrate an important role for m6A methylation in CML and show that targeting the METTL3/METTL14 complex may represent a promising therapeutic strategy for TKIs resistant CML cells

miR-23a and miR-125b regulate neural stem/progenitor cell proliferation by targeting Musashi1.

Abstract Musashi1 is an RNA binding protein that controls the neural cell fate, being involved in maintaining neural progenitors in their proliferative state. In particular, its downregulation is needed for triggering early neural differentiation programs. In this study, we profiled microRNA expression during the transition from neural progenitors to differentiated astrocytes and underscored two upregulated microRNAs, miR-23a and miR-125b, that sinergically act to restrain Musashi1 expression, thus creating a regulatory module controlling neural progenitor proliferation

New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m(6)A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML

Mir-23a and mir-125b regulate neural stem/progenitor cell proliferation by targeting Musashi1

<div><p>Musashi1 is an RNA binding protein that controls the neural cell fate, being involved in maintaining neural progenitors in their proliferative state. In particular, its downregulation is needed for triggering early neural differentiation programs. In this study, we profiled microRNA expression during the transition from neural progenitors to differentiated astrocytes and underscored 2 upregulated microRNAs, miR-23a and miR-125b, that sinergically act to restrain Musashi1 expression, thus creating a regulatory module controlling neural progenitor proliferation.</p></div