Cross-lingual semantic annotation of biomedical literature: experiments in Spanish and English.

MOTIVATION: Biomedical literature is one of the most relevant sources of information for knowledge mining in the field of Bioinformatics. In spite of English being the most widely addressed language in the field; in recent years, there has been a growing interest from the natural language processing community in dealing with languages other than English. However, the availability of language resources and tools for appropriate treatment of non-English texts is lacking behind. Our research is concerned with the semantic annotation of biomedical texts in the Spanish language, which can be considered an under-resourced language where biomedical text processing is concerned. RESULTS: We have carried out experiments to assess the effectiveness of several methods for the automatic annotation of biomedical texts in Spanish. One approach is based on the linguistic analysis of Spanish texts and their annotation using an information retrieval and concept disambiguation approach. A second method takes advantage of a Spanish-English machine translation process to annotate English documents and transfer annotations back to Spanish. A third method takes advantage of the combination of both procedures. Our evaluation shows that a combined system has competitive advantages over the two individual procedures. AVAILABILITY AND IMPLEMENTATION: UMLSMapper (https://snlt.vicomtech.org/umlsmapper) and the annotation transfer tool (http://scientmin.taln.upf.edu/anntransfer/) are freely available for research purposes as web services and/or demos. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation.

Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of MMSET by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.

The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling.

The tricarboxylic acid cycle enzyme fumarate hydratase (FH) has been identified as a tumor suppressor in a subset of human renal cell carcinomas. Human FH-deficient cancer cells display high fumarate concentration and ROS levels along with activation of HIF-1. The underlying mechanisms by which FH loss increases ROS and HIF-1 are not fully understood. Here, we report that glutamine-dependent oxidative citric acid cycle metabolism is required to generate fumarate and increase ROS and HIF-1 levels. Accumulated fumarate directly bonds the antioxidant glutathione in vitro and in vivo to produce the metabolite succinated glutathione (GSF). GSF acts as an alternative substrate to glutathione reductase to decrease NADPH levels and enhance mitochondrial ROS and HIF-1 activation. Increased ROS also correlates with hypermethylation of histones in these cells. Thus, fumarate serves as a proto-oncometabolite by binding to glutathione which results in the accumulation of ROS.

EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation.

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.

Total kinetic analysis reveals how combinatorial methylation patterns are established on lysines 27 and 36 of histone H3.

We have developed a targeted method to quantify all combinations of methylation on an H3 peptide containing lysines 27 and 36 (H3K27-K36). By using stable isotopes that separately label the histone backbone and its methylations, we tracked the rates of methylation and demethylation in myeloma cells expressing high vs. low levels of the methyltransferase MMSET/WHSC1/NSD2. Following quantification of 99 labeled H3K27-K36 methylation states across time, a kinetic model converged to yield 44 effective rate constants qualifying each methylation and demethylation step as a function of the methylation state on the neighboring lysine. We call this approach MS-based measurement and modeling of histone methylation kinetics (M4K). M4K revealed that, when dimethylation states are reached on H3K27 or H3K36, rates of further methylation on the other site are reduced as much as 100-fold. Overall, cells with high MMSET have as much as 33-fold increases in the effective rate constants for formation of H3K36 mono- and dimethylation. At H3K27, cells with high MMSET have elevated formation of K27me1, but even higher increases in the effective rate constants for its reversal by demethylation. These quantitative studies lay bare a bidirectional antagonism between H3K27 and H3K36 that controls the writing and erasing of these methylation marks. Additionally, the integrated kinetic model was used to correctly predict observed abundances of H3K27-K36 methylation states within 5% of that actually established in perturbed cells. Such predictive power for how histone methylations are established should have major value as this family of methyltransferases matures as drug targets.

The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells.

The multiple myeloma SET domain (MMSET) protein is overexpressed in multiple myeloma (MM) patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/Wolf-Hirschhorn syndrome candidate 1 in development, its mode of action in the pathogenesis of MM is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth, and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation, and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.

Repetitive nicotine exposure leads to a more malignant and metastasis-prone phenotype of SCLC: a molecular insight into the importance of quitting smoking during treatment.

Cigarette smoking is strongly correlated with the onset of lung cancer. Nicotine, a major component in cigarette smoke, has been found to promote tumor growth and angiogenesis, as well as protect cancer cells from apoptosis. Among all lung cancer cases, small cell lung cancer (SCLC) is found almost exclusively in smokers; metastasis and chemoresistance are the main reasons for the high mortality rates associated with SCLC. Retrospective studies have shown that patients with tobacco-related cancers who continue to smoke after their diagnosis display lower response rates and a shorter median survival compared with those who stop smoking. In the current work, we examined the effects of acute and repetitive exposure to nicotine, in the concentrations found in the lungs of active smokers, on the malignant properties of N417 SCLC cells in vitro. We observed that repetitive nicotine exposure induced a neuronal-like appearance in N417 cells along with increased adhesion to the extracellular matrix and chemoresistance. These changes were accompanied by enhanced migration through collagen matrices and adhesion to and transmigration across lymphatic endothelial cell monolayers. SCLC differentiation reverted after cessation of nicotine exposure. Here, we provide evidence for the leading role of the CXCR4/CXCL12 axis in these phenomena. Finally, we show how nicotine-differentiated N417 cells produced bigger and more vascularized tumors in mice, with lower apoptotic rates, than their nondifferentiated counterparts. In short, these findings identify the mechanisms through which nicotine increases SCLC malignancy and provide further evidence that CXCR4 is a potential anticancer target for nicotine-associated SCLC.

Deregulation of H3K27 methylation in cancer.

A new study now reports recurrent somatic mutation of EZH2, a histone methyltransferase that modifies H3K27, in diffuse large B-cell lymphoma (DLBCL). There is now evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in cancer, suggesting that a precise balance of this methylation is critical for normal cell growth.

Recurrent exposure to nicotine differentiates human bronchial epithelial cells via epidermal growth factor receptor activation.

Cigarette smoking is the major preventable cause of lung cancer in developed countries. Nicotine (3-(1-methyl-2-pyrrolidinyl)-pyridine) is one of the major alkaloids present in tobacco. Besides its addictive properties, its effects have been described in panoply of cell types. In fact, recent studies have shown that nicotine behaves as a tumor promoter in transformed epithelial cells. This research focuses on the effects of acute repetitive nicotine exposure on normal human bronchial epithelial cells (NHBE cells). Here we show that treatment of NHBE cells with recurrent doses of nicotine up to 500 muM triggered cell differentiation towards a neuronal-like phenotype: cells emitted filopodia and expressed neuronal markers such as neuronal cell adhesion molecule, neurofilament-M and the transcription factors neuronal N and Pax-3. We also demonstrate that nicotine treatment induced NF-kB translocation to the nucleus, phosphorylation of the epidermal growth factor receptor (EGFR), and accumulation of heparin binding-EGF in the extracellular medium. Moreover, addition of AG1478, an inhibitor of EGFR tyrosine phosphorylation, or cetuximab, a monoclonal antibody that precludes ligand binding to the same receptor, prevented cell differentiation by nicotine. Lastly, we show that differentiated cells increased their adhesion to the extracellular matrix and their protease activity. Given that several lung pathologies are strongly related to tobacco consumption, these results may help to better understand the damaging consequences of nicotine exposure.