Littérature scientifique sur le sujet « Alternative last exon (ALE) »

ELAV/Hu factors are conserved RNA binding proteins (RBPs) that play diverse roles in mRNA processing and regulation. The founding member,DrosophilaElav, was recognized as a vital neural factor 35 years ago. Nevertheless, little was known about its impacts on the transcriptome, and potential functional overlap with its paralogs. Building on our recent findings that neural-specific lengthened 3’ UTR isoforms are co-determined by ELAV/Hu factors, we address their impacts on splicing. While only a few splicing targets ofDrosophilaare known, ectopic expression of each of the three family members (Elav, Fne and Rbp9) alters hundreds of cassette exon and alternative last exon (ALE) splicing choices. Reciprocally, double mutants ofelav/fne, but notelavalone, exhibit opposite effects on both classes of regulated mRNA processing events in larval CNS. While manipulation ofDrosophilaELAV/Hu RBPs induces both exon skipping and inclusion, characteristic ELAV/Hu motifs are enriched only within introns flanking exons that are suppressed by ELAV/Hu factors. Moreover, the roles of ELAV/Hu factors in global promotion of distal ALE splicing are mechanistically linked to terminal 3’ UTR extensions in neurons, since both processes involve bypass of proximal polyadenylation signals linked to ELAV/Hu motifs downstream of cleavage sites. We corroborate the direct action of Elav in diverse modes of mRNA processing using RRM-dependent Elav-CLIP data from S2 cells. Finally, we provide evidence for conservation in mammalian neurons, which undergo broad programs of distal ALE and APA lengthening, linked to ELAV/Hu motifs downstream of regulated polyadenylation sites. Overall, ELAV/Hu RBPs orchestrate multiple broad programs of neuronal mRNA processing and isoform diversification inDrosophilaand mammalian neurons.

Abstract Abstract 2392 In humans, the majority of all protein-coding transcripts contain introns that are removed by mRNA splicing carried out by spliceosomes. Mutations in the spliceosome machinery have recently been identified using whole-exome/genome technologies in myelodysplastic syndromes (MDS) and in acute myeloid leukemia (AML). In MDS the frequency of somatic spliceosomal mutations (SSM) range from 1–3% for U2AF1 in RARS/RCMD-RS to more than 70% for SF3B1 in ARSI. These values are significantly lower in AML whereas AML cells cumulate numerous splicing defects. Beside SSMs, one can propose that alternative splicing (AS) might be disturbed by other processes such as abnormal protein-protein interactions. DEK and WT1 are 2 oncogenes overexpressed in most patients with AML. They physiologically influence AS through physical interactions with the heterodimer U2AF1/U2AF2 involved in the recognition of splice acceptor site by the splicing machinery. It is therefore possible that the leukemogenic overexpression of DEK or WT1 might deregulate AS in AML cells, even in the absence of SSM. Here we show that DEK and WT1 affect AS in AML cells. Exon expression profiling was performed in triplicate with MOLM13, KASUMI and KG1 AML cells stably knocked down or not for DEK and WT1 through shRNA. The efficiency of shRNA-mediated silencing was confirmed by western blot and total RNA was analyzed using the Exon microarray platform GeneChip Human Exon 1.0 ST (Affymetrix). Microarray data were cross-compared between cell lines and only statistically significant modifications (p<0.05) shared by MOLM13, KASUMI and KG1 cells were selected. DEK and WT1 knock-down induced the transcriptional deregulation of 1613 (813 up) and 3280 (998 up) genes in AML cell lines, respectively. AS events were selected and annotated with fasterDB database (http://fasterdb.com/faster/home.pl) for genes displaying either no or low (<2) differential transcription. With this approach, differential expression of DEK coincided with changes in 1049 AS events over 934 genes. Those were distributed in 4 alternative acceptor sites (ACC), 222 first exons (AFE), 257 last exons (ALE), 539 spliced exon (ASE), 6 deletions (DEL), 21 donor sites (DON). Differential expression of WT1 led to modifying 1371 alternative splicing entities over 1198 genes. Those were distributed in 6 ACC, 385 AFE, 343 ALE, 590 ASE, 13 DEL, and 34 DON. Genes with AS events were then sorted based on gene function with DAVID bioinformatics resources version 6.7 (http://david.abcc.ncifcrf.gov/). The results indicated that, in both DEK- and WT1-dependent assays, a large subset of genes were related to hematopoietic cell lineage followed by other functional categories such as calcium signaling, ATP-binding cassette (ABC) transporters, and focal adhesion pathways that have been previously reported to be affected in AML cells and involved in resistance to chemotherapy. Differential expression of WT1 modified AS of CD3E, CD9, CSF1R, CSF3R, CR2, GP1BA, ITGA1, ITGA3, ITGB3, IL1A and IL6 while that of DEK led to modulate AS of CD19, CD1d, CD36, CD3G, CSF1R, CR2, ITGA1, ITGA2B, ITGA4, ITGA6, IL7, HLA-DRB5, and MME. Microarray data were validated by exon specific RT-PCR. Exon expression profiling of fresh AML bone marrow samples with or without U2AFs mutations and various levels of DEK or WT1 expression is currently in progress and will be presented. In conclusion in AML cells, DEK and WT1 overexpression affects AS of numerous key genes involved in hematologic differentiation, leukemogenesis and resistance to chemotherapy. These posttranscriptional effects occur in the absence of transcriptional change and therefore highlight hitherto unknown phenotypic alterations having putative diagnostic, prognostic and therapeutic interests. DEK and WT1 are overexpressed in more than 80% of AML and target AS via U2AFs that are mutated in only 0–8% of cases. Accordingly present results strongly suggest that other factors than SSM divert AS in AML. Disclosures: No relevant conflicts of interest to declare.

Expression of cytochrome P450 mRNA in rat germ cells was characterized by reverse transcription PCR with various primers located at the 3'-end of the coding region. At least two unusual isoforms (Ex10-S and INT) of P450 aromatase (P450arom) mRNA were expressed. Analysis of their sequences demonstrated that an alternative splicing event occurred first at the exon-intron boundary of the GT consensus sequence of the last coding exon, and second in the internal 5' donor inside exon 9 used as a minor cryptic splicing site. These isoforms lacked the last coding exon which contained the heme-binding domain; in addition, for the Ex10-S transcript, the catalytic domain was also absent because of a frameshift in the open reading frame. The deduced amino acid sequences led to truncated P450arom polypeptides without the heme-binding domain, which were probably unable to convert androgens into estrogens. Adult rat germ cells are able to express P450arom mRNA, which is then translated into a biologically active enzyme which is involved in estrogen production. Moreover, for the first time, we report the existence of alternative splicing events of P45Oarom mRNA in pachytene spermatocytes and round spermatids, which probably cannot encode functional aromatase molecules.

Skeletal muscle, accounting for approximately 50% of body weight, is the largest and most important tissue. In this study, the gene expression profiles and pathways in skeletal muscle of Pekin duck were investigated and compared at embryonic day 17, 21, and 27 and postnatally at 6 months of age. An average of 49,555,936 reads in each sample was obtained from the transcriptome libraries. Over 70.0% of alternative splicing (AS) in each sample was mainly alternative 5′ first exon (transcription start site)—the first exon splicing (TSS) and alternative 3′ last exon (transcription terminal site)—the last exon splicing (TTS), indicating that TSS and TTS were the most common AS event in Pekin ducks, and these AS events were closely related to the regulation of muscle development at different growth stages. The results provided a valuable genomic resource for selective breeding and functional studies of genes. A total of 299 novel genes with ≥2 exons were obtained. There were 294 to 2806 differentially expressed genes (DEGs) in each pairwise comparison of Pekin duck. Notably, 90 DEGs in breast muscle and 9 DEGs in leg muscle were co-expressed at all developmental points. DEGs were validated by qPCR analysis, which confirmed the tendency of the expression. DEGs related to muscle development were involved in biological processes such as “endodermal cell differentiation”, “muscle cell cellular homeostasis”, “skeletal muscle tissue growth” and “skeletal muscle cell differentiation”, and were involved in pathways such as oxidative phosphorylation, ECM-receptor (extracellular matrix receptor) interaction, focal adhesion, carbon metabolism, and biosynthesis of amino acids. Some DEGs, including MYL4, IGF2BP1, CSRP3, SPP1 and KLHL31, as well as LAMB2, LAMA2, ITGB1 and OPN, played crucial roles in muscle growth and development. This study provides valuable information about the expression profile of mRNAs and pathways from duck skeletal muscle at different growth stages, and further functional study of these mRNAs and pathways could provide new ideas for studying the molecular networks of growth and development in duck skeletal muscle.

SummaryAmplification and sequencing of exons I-XV of the gene encoding subunit A of coagulation factor XIII (FXIII) in a patient with severe subunit A deficiency revealed a single G → A base substitution at the last position of intron E, mutating the invariant AG dinucleotide splice acceptor site to AA. Northern blot analysis of FXIII subunit A mRNA levels in peripheral mononuclear leukocytes showed that this mutation leads to an undetectable FXIII subunit A mRNA level, suggesting that the mutant transcript is either highly unstable or only spliced at low efficiency. Despite this low mRNA level we were able to amplify cDNA fragments containing the exonV-exonVI junction. Sequence analysis showed that the AA dinucleotide is not recognized by the splicing machinery. Instead, an AG dinucleotide located seven bases downstream of the mutated splice acceptor site is used as alternative acceptor. The resulting, alternatively spliced, FXIII subunit A transcript contains a deletion of the first seven bases of exon VI, while translation continues out of frame and leads to a premature stop codon 27 bases thereafter.

Abstract hTERT, a telomere specific reverse transcriptase with a crucial role in telomerase activity, prevents telomeres shortening, a pro-apototic cellular event which occurs at every round of DNA replication. Its regulation is complex as alternative spliced variants which generate the full-length hTERT transcript (+α+β) and transcripts carrying α and/or β deletions (transdominant negative isoform -α+β, inactive products +α-β and -α-β) have been reported. In AML the prognostic significance of hTERT expression is still debated, even if its over-expression has been correlated with a poor clinical outcome. In contrast, up to now no study has dealt with the frequency and the prognostic significance of variant transcripts. Thus, our study was aimed at estimating hTERT isoforms distribution in a series of de novo AML patients (pts), at establishing whether their expression varied between pts with a normal and a complex chromosome pattern, at estimating their prognostic significance. The ninety-seven de novo AML pts included in the present study came to our observation in the period January 2010 and January 2013. They were thirty-eight females and fifty-nine males; their median age was 59 years (range 18-84). On conventional cytogenetic studies fifty-two, whose median age was 56 years (range 24-84), presented a normal karyotype and forty-five, whose median age was 60 years (range 33-84), presented a complex karyotype (≥3 defects); the two pts groups were comparable by age. According to WHO classification 6 (6.1%) pts were classified as M0/M1, 47 (48.4%) as M2, 38 (39.1%) as M4, 5 (5.1%) as M5 and one as M6. An internal tandem duplication (ITD) of the FLT3 gene and a NPM1 mutation were revealed in 12 and 2 chromosomally normal pts. No CK presented a FLT3 ITD. All pts received standard induction chemotherapy followed by two courses of consolidation treatment. At the time of the study 38 pts achieved a complete remission (CR) and 36 died. Median follow-up was 22.7 months (range: 13.5-60.2). hTERT isoforms expression was determined in bone marrow samples by real-time reverse transcriptase polymerase chain reaction, using SYBR Green I. hTERT transcript (+α+β) primers’ design was made using BLAST (http://www.ncbi.nlm.nih.gov/BLAST/), while for the other primers we referred to Capraro et al. 2011. Specific amplifications were confirmed by sequences analysis. In order, to estimate hTERT isoforms expression levels in normal mononuclear cells, twenty-three umbilical cord bloods (UCB) were examined (control group). When the Kruskal-Wallis rank test was applied to compare the expression of hTERT isoforms inAML pts with a normal and a complex karyotype no significant difference was observed (P=0.39, P=0.77; +α+β, -α+β respectively). Instead, independently from karyotype, in Cox univariate analysis, pts who over-expressed the trans-dominant negative isoform (-α+β) experienced a significant better response to treatment than the other pts (P=0.03, HR=2.11; 95% CI:1,13-3,93). In addition, pts who over-expressed inactive products (-α-β) (first group) presented a leukemia-free survival inferior to that of pts who presented a low expression of these products (second group) (P=0,003, HR=3,26; 95% CI:1,33-7,96). Moreover, pts who over-expressed the full-length hTERT transcript (+α+β) and the trans-dominant negative isoform (-α+β) presented only a trend towards significance. The first group of pts presented a worse overall survival (HR=1,66; 95% CI:0.94-2,91), whereas the second group a better overall survival (HR=0,58; 95% CI:0,33-1,02). We conclude that the over-expression of the hTERT trans-dominant negative isoform identifies pts with low-risk AML, whereas the over-expression of the hTERT inactive product (-α-β) identifies pts with high-risk AML. In addition, this last hTERT isoform might control the expression of its trans-dominant negative isoform. Thus, our results suggest an intriguing link between the control of hTERT isoforms expression and AML outcome. Disclosures No relevant conflicts of interest to declare.

Rare pathogenic variants in the MYH11 gene are responsible for thoracic aortic aneurysms and dissections. They are usually heterozygous missense variants or in-frame deletions of several amino acids without alteration of the reading frame and mainly affect the coiled-coil domain of the protein. Variants leading to a premature stop codon have been described in patients with another phenotype, megacystis-microcolon-intestinal hypoperistalsis syndrome, with an autosomal recessive inheritance. The physiopathological mechanisms arising from the different genetic alterations affecting the MYH11 gene are still poorly understood. Consequently, variants of unknown significance are relatively frequent in this gene. We have identified a variant affecting the consensus donor splice site of exon 29 in the MYH11 gene in a patient who suddenly died from an aortic type A dissection at the age of 23 years old. A transcript analysis on cultured fibroblasts has highlighted several abnormal transcripts including two in-frame transcripts. The first one is a deletion of the last 78 nucleotides of exon 29, corresponding to the use of a cryptic alternative donor splice site; the second one corresponds to an exon 29 skipping. Familial screening has revealed that this molecular event occurred de novo in the proband. Taken together, these experiments allowed us to classify this variant as pathogenic. This case underlines the challenging aspect of the discovery of variations in the MYH11 gene for which the consequences on splicing should be systematically studied in detail.

Abstract The Ankyrin (ANK)-repeat is one of the most common protein sequence motifs, which leads itself to variation in overall domain size by simple sequence duplication or deletion. The Mask (Multiple Ankyrin Repeats Single KH domain) gene, which codifies an ANK-repeat protein, is located in chromosome 5(q31.3) and it is composed of 39 exons. It generates isoforms by alternative 3′splicing. The first splice variant (hMask) lacks the 10A exon of the Mask gene, generating a mRNA containing 34 exons. The other, Mask-BP3ARF, results from fusion of splice variant hMask, with the two last exons of the gene Eif4Ebp3 (exons B and C) and an intermediate exon (exon 0), generating 36 exons. Recently, a new splice variant, denominated PP2500, was deposited in the data base GeneBank, it presents the first 10 exons, homologous to Mask mRNA with a poly(A+) signal and it is a new splice variant of Mask. In Drosophila, MASK protein seems to interact with members of the Receptor Tyrosine Kinase (RTK) signalling pathway and loss of this interaction increases programmed cell death, reduces cell proliferation, inhibits photoreceptor differentiation, affects RTK dependents processes but does not affect MAPK (Mitogen Activated Protein Kinase) activation. However, the biological functions of these proteins in humans remain still unknown. The aim of this study was to investigate the expression of Mask splice variants in multiple myeloma (MM). Fifteen patients with MM and 3 normal donors participated in this study. Total RNA was extracted from positively selected plasma cells in magnetic column, by Macs Microbeads antibody anti-CD138 and the percentage of purity of plasma cells varied from 78.38% to 96.02% (average 87.95%). We used as control, total RNA from positively selected plasma cells, from a culture of B normal lymphocytes of bone marrow donors (purity 88.69%). The complementary DNA (cDNA) was analyzed by Real-time detection of amplification, performed in an ABI 5700 Sequence Detector System using SybrGreen PCR Master Mix (qPCR). The b-actin gene was used as endogenous control of the reaction. The mean expression of the mRNA of the hMask and Mask-BP3ARF genes were 3 and 4 times increased, respectively, compared with control. The mean expression of the PP2500 mRNA was 14 times increased, compared with control. Quantification of hMask, Mask-BPARF and PP2500 mRNA was not influenced by age, gender, ethnic origin, stage of the disease, β2-microglobulin, serum creatinine and lactate dehydrogenase values (Fisher’s exact test, P&gt; 0.05). Previously we demonstrated that MASK is associated with SHP2, a protein tyrosine-phosphatase. In MM, SHP2 mediates the anti-apoptotic effect of Interleukin-6 (Chauhan et al. JBC275: 27845, 2000). Interleukin-6 triggers proliferation of MM cells via the MAPK cascade, which includes SHP2 activation. Thus, the increased expression of Mask splice variants in plasma cells of MM suggests that their proteins may be involved in this signaling pathway and provide an insight for novel treatment approaches in MM. Supported by FAPESP and CNPq

11536 Background: Despite long-lasting responses to imatinib most metastatic gastrointestinal stromal tumors (GIST) eventually progress and subsequent treatments are associated with limited duration of disease control. Ponatinib is a potent KIT inhibitor with a strong activity against secondary mutations in exon 17, including the highly resistant D816 mutations of KIT. Based on the dose-depending toxicity profile we sought to evaluate the safety and activity of lower dosing (30mg) ponatinib in pretreated patients with KIT-mutant GIST. We here report safety data for the whole cohort and first efficacy data for the last line cohort within a planned interim analysis. Methods: This multicenter phase 2 trial (NCT03171389) recruited patients with advanced, unresectable GIST progressing after imatinib (Cohort A/B: absence/presence of KIT Exon 13/14 mutations by plasma sequencing) or imatinib, sunitinib and regorafenib (Cohort C). Patients were treated with 30mg oral ponatinib daily in 4-week-cycles. The primary endpoint was the clinical benefit rate at 16 weeks as measured by mRECIST1.1 criteria. Results: At the cutoff date of 31st Jan 2020, 39 patients were evaluable for safety analysis (25 male, 14 female, median age 60 (38-86) years). Median duration of treatment was 65 (14-699) days. 66.7% of all patients observed Grade 3/4 adverse events (AEs), most common were pain (10/39), hypertension (6/39), GGT or lipase increase (both 5/39), and fever (3/39). One AE of special interest was observed (myocardial infarction, rated not related to study drug) and 20/39 patients experienced at least 1 severe AE (6/39 possibly related to ponatinib). Within the last line cohort, 20 patients were evaluable for efficacy. Clinical benefit rate was 35% (CI 15.4-59.2%). Median progression-free survival was 86 days with single patients yielding long-lasting responses (75% quartile 210 days, maximum: 420 days). Conclusions: Treatment with ponatinib was tolerable at a dose of 30mg qd with a toxicity profile comparable to other TKIs used in GIST. The majority of grade 3/4 AEs were hypertension or asymptomatic increases of laboratory values and thromboembolic events were rare. In a heavily pretreated patient population that lacks alternative treatment options the clinical activity was notable. An updated analysis including predictive biomarkers will be presented. Clinical trial information: NCT03171389 .

The structure of the Drosophila melanogaster tropomyosin II (TmII) gene has been determined by DNA sequencing of cDNA clones and the genomic DNA coding for the gene. Two overlapping transcriptional units produce at least four different tropomyosin isoforms. A combination of developmentally regulated promoters and alternative splicing produces both muscle and cytoskeletal tropomyosin isoforms. One promoter is a muscle-specific promoter and produces three different tropomyosin isoforms by alternative splicing of the last three 3' exons. The second promoter has the characteristics of a housekeeping promoter and produces a cytoskeletal tropomyosin isoform. Several internal exons along with a final 3' exon are alternatively spliced in the cytoskeletal transcript. The intron-exon boundaries of the TmII gene are identical to the intron-exon boundaries of all vertebrate tropomyosin genes reported, but are very different from the intron-exon boundaries of the D. melanogaster tropomyosin I gene. The TmII gene is the only reported tropomyosin gene that has two promoters and a quadruple alternative splice choice for the final exon. Models for the mechanism of D. melanogaster tropomyosin gene evolution are discussed.

Le syndrome de Li-Fraumeni (LFS) prédispose les porteurs de variations pathogènes de TP53 à un large spectre de tumeurs dès l’enfance. La variabilité phénotypique du LFS complique la prise en charge des patients et peut s’expliquer en partie par le type de variations de TP53, mais également par l'influence de facteurs modificateurs génétiques. Afin d’évaluer ces facteurs modificateurs, il est nécessaire de mettre au point des tests fonctionnels adaptés.L’activité des isoformes de p53 suggère qu’elles pourraient agir comme facteurs modificateurs du LFS. C’est pourquoi nous avons mis au point des techniques pour l’analyse des transcrits alternatifs, présentées dans la première partie de ces travaux de thèse. Si nos résultats ont montré que ces techniques n’étaient pas adaptées pour répondre à cette hypothèse, elles nous ont néanmoins permis d’identifier un nouveau transcrit physiologique, non décrit dans la littérature, augmenté chez une patiente porteuse d’une variation située sur le site accepteur d’épissage du dernier exon de TP53. Ce transcrit démontre l’existence d’un épissage alternatif du dernier exon de TP53 avec un exon terminal alternatif situé à plus de 2 kb en aval.Afin d’aider à la classification des variations de TP53, notre laboratoire évalue l’activité transcriptionnelle de p53 dans le contexte génétique du patient. Ce test ne permet donc pas de s’affranchir de l’influence potentielle des facteurs modificateurs génétiques individuels. C’est pourquoi, dans la deuxième partie de ces travaux de thèse, nous avons mis au point un modèle cellulaire de cellules souches pluripotentes induites humaines permettant d’étudier les variations de TP53 insérées par CRISPR-Cas9 dans un fond génétique commun. Ces travaux soulignent l’importance de l’expression de TP53, notamment pour l’étude des variations dont la pénétrance est moindre par rapport aux variations « hot-spot ». Par ailleurs, nous montrons que les variations en phase exercent un impact différentiel sur l’activité fonctionnelle de p53, selon le domaine protéique dans lequel elles se situent. L’avantage de notre modèle réside également sur son hétérozygotie pour PEX4 sur lequel nous avons pu insérer une seconde variation, ici le polymorphisme p.(Pro47Ser) inséré en trans d’une variation pathogène. Nos résultats soulignent l’importance du contexte génétique dans l’analyse des variations de TP53. L’ensemble de ces travaux de thèse mettent en lumière la nécessité d’étudier l’activité transcriptionnelle de p53 dans un contexte physiologique, sans surexpression, dans le but de mieux comprendre ce syndrome et d’optimiser la prise en charge des patients LFS
Li-Fraumeni Syndrome (LFS) predisposes carriers of pathogenic TP53 variants to a wide spectrum of cancers throughout life. The phenotypic variability of LFS complicates patient management and can be partly attributed to the type of TP53 variant, as well as the influence of genetic modifier factors. To evaluate these modifier factors, it is essential to develop suitable functional tests.The activity of p53 isoforms suggests that they may act as modifier factors in LFS. Consequently, we developed assays for analyzing alternative transcripts, as presented in the first part of this work. While our results demonstrated that these assays were not well-suited to addressing this specific hypothesis, they nevertheless led us to the discovery of a novel physiological transcript not previously described in the literature. This transcript was found to be increased in a patient carrying a variant located at the splice acceptor site of TP53’s last exon, revealing an alternative splicing event involving TP53’s final exon and an alternative terminal exon located more than 2 kb downstream.To facilitate the classification of TP53 variants, our laboratory evaluates p53’s transcriptional activity in the patient’s specific genetic context. However, this approach does not allow us to fully disentangle the potential influence of individual genetic modifier factors. Therefore, in the second part of this work, we developed a human-induced pluripotent stem cell model to study TP53 variants introduced by CRISPR-Cas9 within a standardized genetic background. Our findings highlight the importance of physiological TP53 expression, particularly for studying variants with lower penetrance compared to "hot-spot" variants. Additionally, we show that in-frame variants exert differential impacts on p53’s functional activity, depending on the protein domain in which they are located. The advantage of our model also lies in its heterozygosity for PEX4, into which we were able to insert a second variant, in this case, the p.(Pro47Ser) polymorphism, inserted in trans with a pathogenic variant. Our results highlight the importance of the genetic context in the analysis of TP53 variants. This thesis work emphasizes the necessity of studying p53 transcriptional activity in a physiological context, without overexpression, with the aim of improving our understanding of this syndrome and optimizing the management of LFS patients

With increasing demand of energy, attention to the alternative sources of sustainable energy is getting priority over the last decades. Offshore wind turbine is one of them. The most widely used foundation system for the wind turbine is the monopile, which is a large diameter single pile. In the present study, three-dimensional finite element (FE) analyses are performed to evaluate the capacity of large diameter monopiles in dense sand using the Arbitrary Lagrangian-Eulerian (ALE) approach available in Abaqus/Explicit FE software. The behavior of sand is modeled using the Mohr-Coulomb (MC) and a modified Mohr-Coulomb (MMC) model where the pre-peak hardening, post-peak softening and the effects of mean effective stress and relative density on stress-strain behavior of dense sand are considered. Comparison with physical model test results shows that the MMC model can simulate better the load-displacement response than that with the MC model. The mechanisms involved in soil deformation are also explained using FE results.