1,720,964 research outputs found
A critical role for the RNA m6A methylation complex in myeloid leukemia
No full textN6-methyladenosine (m6A) is a well-known RNA modification that can affect mRNA splicing, stability and translation (D. Dominissini et al., 2012; X. Wang et al. 2015; Y. Wang et al. 2014; J. Zhou et al. 2015; J. Choi et al. 2016), and the processing of miRNA precursors (C.R. Alarcon et al. 2015). In mammals, the m6A writer is a multicomponent complex composed of the two methyltransferases METTL3 and METTL14 (J. Liu et al. 2014), and the regulatory protein WTAP (XL. Ping et al. 2014). Post-transcriptional m6A RNA modification is indispensable for cell viability and development, yet its role in cell differentiation and disease are still poorly understood. Notably, WTAP protein is an oncogene overexpressed in Acute Myeloid Leukemia (AML) compared to healthy control cells (H. Bansal et al., 2014). Moreover, METTL3, METTL14, and RBM15 are highly expressed in AML compared with other cancers (S.R. Jaffrey and M G. Kharas, 2017). We analysed the expression of the m6A RNA methylation complex components in AML observing that both METTL3 and METTL14 mRNAs are upregulated in AML samples (TCGA) respect to fully differentiated myeloid cells (GeoDatasets). Conversely, WTAP mRNA has lower levels in AML, even if the protein is upregulated. We showed that in AML and Chronic Myeloid Leukemia (CML) cell lines METTL3 is localized in both nucleus and cytoplasm. In cytoplasm METTL3 binds WTAP mRNA enhancing its translation independently from its catalytic activity, possibly explaining, at least partially, WTAP protein increased levels observed in AML cells. Moreover, we investigated the role of m6A RNA methylation complex components in myeloid leukemia cells, confirming that WTAP affects proliferation and differentiation of AML cells acting as an oncogene and demonstrating that METTL3 and METTL14 are essential proteins in these cells. Indeed, depletion of the two methyltransferases leads to a marked cellular mortality of AML cells. Notably, METTL3 affects viability and proper myeloid differentiation also in hematopoietic stem cells CD34+ derived from healthy umbilical cord. In CML K562 cells METTL3 and METTL14 depletion does not lead to apoptosis but could affect proper ribosome biogenesis, leading to an evident slowdown of cellular proliferation. Notably, decreased levels of METTL3 and METTL14 in K562 cells cause a downregulation of MYC protein, as recently reported in AML cells (L.P. Vu et al., 2017). Analysing ENCODE MYC ChIP- seq data we observed strong MYC peaks on the promoter of all the genes critical for ribosome biogenesis that are affected by METTL3 and METTL14 depletion, suggesting a MYC-mediated effect. In conclusion, we analysed some functional aspects of m6A RNA chemical modification in both acute and chronic myeloid leukemia cells, identifying differential m6A-regulated pathways between these two kinds of pathologies. Moreover, we also highlighted a more complex and double role for METTL3 protein in these cells, being one of the two essential m6A methyltransferase in the nucleus, and an RNA binding protein promoting translation in cytoplasm. Altogether, these data indicate a link between m6A factors and leukemogenesis and pave the way to possible future therapies targeting the RNA m6a methylation complex components
A positive feed-forward regulatory loop between METTL3 and WTAP sustains the oncogenic role of the m6A methylation complex in myeloid leukemia
No full textThe 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
Unraveling the function of m6A modification in acute myeloid leukemia
No full textN6-methyladenosine (m6A) is a well-known RNA modification that can affect mRNA stability and translation (Yue et al., Genes Dev. 2015). In mammals, the m6A writer is a multicomponent complex composed of the two methyltransferases METTL3 and METTL14 and the regulatory protein WTAP. WTAP has been recently described as an oncogenic factor in AML suggesting that m6A modification might play crucial role in leukemogenesis (Bansal et al., Leukemia 2014). Notably, we also found that METTL3 and METTL14 are upregulated in primary AML samples. Here, we analyzed the functional role of m6A during myeloid differentiation of AML cell lines. Impairing the expression of the methylation complex components by RNAi affected consistently myeloid differentiation and induced massive apoptosis. Moreover, in AML cell lines METTL3 mislocalized in the cytoplasm and associated with polysomes. These data indicate that the misregulation of m6A methylation may contribute to leukemogenesis, but also highlight a putative m6A-independent role for METTL3. Our data also pave the way to the development of new therapies for AML through the inhibition of the methylome complex
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
METTL3 regulates WTAP protein homeostasis
Full text linkThe 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
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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