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PubMed2006

A genome-based approach to create a minimally mutated Corynebacterium glutamicum strain for efficient L-lysine production.

Based on the progress in genomics, we have developed a novel approach that employs genomic information to generate an efficient amino acid producer. A comparative genomic analysis of an industrial L-lysine producer with its natural ancestor identified a variety of mutations in genes associated with L-lysine biosynthesis. Among these mutations, we identified two mutations in the relevant terminal pathways as key mutations for L-lysine production, and three mutations in central metabolism that resulted in increased titers. These five mutations when assembled in the wild-type genome led to a significant increase in both the rate of production and final L-lysine titer. Further investigations incorporated with transcriptome analysis suggested that other as yet unidentified mutations are necessary to support the L-lysine titers observed by the original production strain. Here we describe the essence of our approach for strain reconstruction, and also discuss mechanisms of L-lysine hyperproduction unraveled by combining genomics with classical strain improvement.

Corynebacterium glutamicum↗

PubMed2004

Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer.

A large fraction of transcripts are expressed antisense to introns of known genes in the human genome. Here we show the construction and use of a cDNA microarray platform enriched in intronic transcripts to assess their biological relevance in pathological conditions. To validate the approach, prostate cancer was used as a model, and 27 patient tumor samples with Gleason scores ranging from 5 to 10 were analyzed. We find that a considerably higher fraction (6.6%, [23/346]) of intronic transcripts are significantly correlated (P< or =0.001) to the degree of prostate tumor differentiation (Gleason score) when compared to transcripts from unannotated genomic regions (1%, [6/539]) or from exons of known genes (2%, [27/1369]). Among the top twelve transcripts most correlated to tumor differentiation, six are antisense intronic messages as shown by orientation-specific RT-PCR or Northern blot analysis with strand-specific riboprobe. Orientation-specific real-time RT-PCR with six tumor samples, confirmed the correlation (P=0.024) between the low/high degrees of tumor differentiation and antisense intronic RASSF1 transcript levels. The need to use intron arrays to reveal the transcriptome profile of antisense intronic RNA in cancer has clearly emerged.

Cell Differentiation↗

PubMed2025

Tonoplast sucrose transporter SUT4-dependent sugar partitioning modulates phenological transitions and reproductive success in poplar.

Climate uncertainty is intensifying the need for greater plasticity in carbohydrate reserve utilization to support winter survival and spring growth in woody perennials. In poplar, the single-copy SUT4, which encodes a tonoplast-localized sucrose transporter, and the SUT5/SUT6 genome duplicates, which encode plasma membrane-localized transporters, are expressed year-round, with SUT4 showing the highest expression during cool seasons. Given its role in vacuolar sucrose efflux and winter-predominant expression, SUT4 may play a key role in modulating seasonal carbohydrate dynamics. While SUT4-knockdown and knockout effects have been studied under greenhouse conditions, their impact under field conditions remains unexplored. Here, we report a field-based study comparing CRISPR knockout mutants of winter-expressed SUT4 and SUT5/SUT6 in Populus tremula × alba. We show that sut4, but not sut5/6, mutants exhibited earlier autumn leaf senescence, delayed spring bud flush, reduced stem growth, and altered sugar partitioning in winter xylem and bark relative to controls. After 2 years in the field, all genotypes flowered before leaf flush in early spring; however, sut4 mutants produced sterile ovules despite developing normal-looking catkins. Metabolic profiling revealed disrupted sucrose and raffinose dynamics in elongating sut4 catkins. This was accompanied by transcriptomic signatures of elevated stress and downregulation of proanthocyanidin biosynthesis and circadian clock genes. These findings highlight the critical role of SUT4 in coordinating sugar allocation, stress responses, and seasonal development in poplar.

Populus↗

PubMed2026

IDH2 clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma.

Lenalidomide, a maintenance treatment in multiple myeloma first-line therapy, increases the risk of secondary malignancies, including B-cell precursor acute lymphoblastic leukemia (B-ALL). We present a comprehensive molecular characterization of 57 patients with lenalidomide-associated B-ALL (LenB-ALL), revealing 3 mutational subgroups: (1) TP53mt (30%); (2) IDH2mt (p.R140Q) (23%); and (3) other, including NRAS/KRASmt. Remarkably, IDH2 R140Q mutations were highly enriched in LenB-ALL compared with those in primary B-ALL (P< .001). Furthermore, IKZF1 intragenic deletions, often subclonal and likely RAG recombinase-mediated, were observed in 54% (7/13) of IDH2mt patients with LenB-ALL. IDH2 mutations were not restricted to the leukemic clone: they persisted during measurable residual disease-negative remission and were identified in lymphoid as well as myeloid cell populations using fluorescence-activated cell sorting and single-cell RNA sequencing. This indicates a preleukemic origin of the IDH2 mutation within the context of clonal hematopoiesis. Transcriptomic and DNA methylation analyses revealed a distinct gene expression profile and a DNA hypermethylation phenotype in IDH2mt LenB-ALL, including IDH2mt-specific as well as lenalidomide-associated features. We propose that lenalidomide promotes the expansion of IDH2-mutated clonal hematopoiesis and, via IKAROS downregulation, induces a maturation arrest at the B-cell precursor stage. Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. All these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.

Humans↗

PubMed2006

Transcriptional and structural impact of TATA-initiation site spacing in mammalian core promoters.

BACKGROUND: The TATA box, one of the most well studied core promoter elements, is associated with induced, context-specific expression. The lack of precise transcription start site (TSS) locations linked with expression information has impeded genome-wide characterization of the interaction between TATA and the pre-initiation complex. RESULTS: Using a comprehensive set of 5.66 x 10(6) sequenced 5' cDNA ends from diverse tissues mapped to the mouse genome, we found that the TATA-TSS distance is correlated with the tissue specificity of the downstream transcript. To achieve tissue-specific regulation, the TATA box position relative to the TSS is constrained to a narrow window (-32 to -29), where positions -31 and -30 are the optimal positions for achieving high tissue specificity. Slightly larger spacings can be accommodated only when there is no optimally spaced initiation signal; in contrast, the TATA box like motifs found downstream of position -28 are generally nonfunctional. The strength of the TATA binding protein-DNA interaction plays a subordinate role to spacing in terms of tissue specificity. Furthermore, promoters with different TATA-TSS spacings have distinct features in terms of consensus sequence around the initiation site and distribution of alternative TSSs. Unexpectedly, promoters that have two dominant, consecutive TSSs are TATA depleted and have a novel GGG initiation site consensus. CONCLUSION: In this report we present the most comprehensive characterization of TATA-TSS spacing and functionality to date. The coupling of spacing to tissue specificity at the transcriptome level provides important clues as to the function of core promoters and the choice of TSS by the pre-initiation complex.

Animals↗

PubMed2026

Sex and tissue resolved co-expression networks reveal a female placental-brain axis protective against prenatal PCB exposure.

BACKGROUND: Neurodevelopmental disorders have a strong male bias that is poorly understood. The placenta provides molecular information about environmental interactions with genetics (including biological sex) that shape developmental processes in the brain. We investigate placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). RESULTS: To understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta RNAseq data, we use weighted gene correlation network analysis (WGCNA) to create gene networks that could be compared across sex or tissue. WGCNA reveals that expression within most correlated gene networks is significantly and strongly associated with PCB exposure, but frequently in opposite directions between male-female and placenta-brain comparisons. In WGCNA and differentially expressed gene analyses, more transcriptional changes are observed in male brain than placenta, but the reverse is seen in females. Furthermore, female X-inactive specific transcript (Xist) levels correlate with sex-specific and non-monotonic PCB dose response, suggesting an X-linked protective epigenetic mechanism. The transcriptomic effects of low-dose PCB exposure are significantly opposed by dietary folic acid supplementation across both sexes but are strongest in female placentas. PCB and folic acid interacting gene networks are enriched in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipid, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. CONCLUSIONS: A female protective effect in response to prenatal PCB exposure appears to be mediated by dose-dependent sex differences in transcriptional modulation of placental metabolic pathways.

Female↗

PubMed2025

Altered ruminal microbiome tryptophan metabolism and their derived 3-indoleacetic acid inhibit ruminal inflammation in subacute ruminal acidosis goats.

BACKGROUND: Subacute ruminal acidosis (SARA) is a digestive disorder that often severely jeopardizes the health and lactation performance of ruminants fed a high-energy diet. Different dairy ruminants exhibit varying degrees of inflammation accompanied by variations in the rumen microbiota when SARA occurs. Our understanding of the occurrence of SARA and varying degrees of rumen epithelial inflammation is lacking. Hence, we performed rumen metagenomic, metagenome-assembled genome and metabolomic analyses, with transcriptome and single-nucleus RNA sequence analyses, to explore the microbial mechanism of SARA occurrence and different degrees of inflammation. RESULTS: A total of 36 goats fed two diets with gradually increasing levels of rumen-degradable starch (RDS) were included in this study, and SARA goats fed 70% concentrate diets supplemented with whole corn (HGW-SARA) and SARA goats fed 70% concentrate diets supplemented with crushed corn (HGC-SARA) were identified. Moreover, 11 goats fed a control basal diet, named LGW-CON, were also included. Compared with those in the LGW-CON group, the rumen fermentation capacity was enhanced, accompanied by ruminal epithelial and systemic inflammation, in goats from HGW-SARA and HGC-SARA. Between them, HGC-SARA goats presented less inflammation. Notably, the ruminal inflammation-related pathways were increased only in the HGW-SARA group but not in the HGC-SARA group. Metagenomic analysis revealed that the β diversity of SARA goats was significantly different from that of LGW-CON goats. Ruminococcus significantly increased in both SARA groups, whereas Prevotella and Bacteroidales significantly decreased, which was accompanied by a decrease in cellulose and hemicellulose enzymes and an increase in lysozymes and lipopolysaccharide synthesis enzymes. Multi-omics analysis of the ruminal contents and tissues suggested that epithelial inflammation was caused by disturbed ruminal microbiome-induced Th17 cell differentiation and IL-17 signalling pathway activation. Comparative analyses between the HGW-SARA and HGC-SARA groups highlighted the importance of Selenomonas and Bifidobacterium, as well as bacterial tryptophan metabolism, in the production of 3-indoleacetic acid, which mitigated ruminal epithelial inflammation by modulating Th17 cells and inhibiting IL-17 signalling. Ruminal microbiota transplantation from HGW-SARA goats to healthy dairy goats and mice revealed the role of microbes in epithelial inflammation. Additionally, 3-indoleacetic acid supplementation reduced rumen inflammation and the IL-17 concentration in the serum, improved VFAs absorption, and enhanced milk production. CONCLUSIONS: This study unveiled that after SARA was induced by high-concentrate feeding, the rumen homeostasis was disrupted, and rumen fiber degradation capacity of dairy goats decreased, but the LPS synthesis capacity increased, and inflammation of the rumen epithelium was observed. However, the ruminal microbial species from the Bifidobacterium and Selenomonas genera and bacterial 3-indole acetic acid are pivotal in mitigating ruminal epithelial inflammation during SARA in dairy goats. This could potentially be attributed to the modulation of ruminal Th17 cell proportions and the inhibition of IL-17 signalling pathways. Video Abstract.

Rumen↗

PubMed2006

Profiling of maternal and developmental-stage specific mRNA transcripts in Atlantic halibut Hippoglossus hippoglossus.

cDNA libraries were constructed from the following developmental stages (tissues) of the Atlantic halibut (Hippoglossus hippoglossus): 2-cell stage (embryos), 1 day-old yolk sac larvae (trunk) and juvenile (fast skeletal muscle). A total of 4249 high quality expressed sequence tags from the three libraries were clustered into a partial transcriptome of 2124 putative genes. A large proportion of the gene clusters (48.3%) had no significant matches against known proteins. The most abundant ESTs of nuclear transcripts in the 2-cell library included sequences with high identity to zebrafish H1M, a linker histone-like protein involved in primordial germ cell specification, zinc finger protein, rRNA external transcribed spacer, thymosin beta-4, cyclin B1 and several predicted peptides from the Tetraodon nigroviridis genome assembly with unknown functions. 170 and 123 ESTs represented ribosomal proteins in the larval and juvenile libraries respectively, compared with only two sequences in the 2-cell library, which may reflect an abundance of maternally inherited pre-formed ribosomes in the yolk. Even though some clusters were common to all three libraries, most putative genes showed a developmental-stage specific distribution with 72% (2-cell embryo), 59% (larval) and 57% (juvenile) sequences having no significant matches against the 8400 adult halibut sequences in the EMBL nucleotide database. Comparison between the predicted halibut peptide data set and the human, zebrafish, and pufferfishes (T. nigroviridis and Takifugu rubripes) proteomes revealed that, as expected, the halibut sequences were more similar to the other two fish species than to human proteins. However, no clear bias towards the pufferfishes was observed, suggesting significant sequence variation between orthologues within the clade Acanthomorpha. The sequence information generated in the present study will represent a significant new resource for future studies on normal and abnormal development in Atlantic halibut.

Animals↗

PubMed2024

Rhinovirus infection of airway epithelial cells uncovers the non-ciliated subset as a likely driver of genetic susceptibility to childhood-onset asthma.

Asthma is a complex disease caused by genetic and environmental factors. Epidemiological studies have shown that in children, wheezing during rhinovirus infection (a cause of the common cold) is associated with asthma development during childhood. This has led scientists to hypothesize there could be a causal relationship between rhinovirus infection and asthma or that RV-induced wheezing identifies individuals at increased risk for asthma development. However, not all children who wheeze when they have a cold develop asthma. Genome-wide association studies (GWAS) have identified hundreds of genetic variants contributing to asthma susceptibility, with the vast majority of likely causal variants being non-coding. Integrative analyses with transcriptomic and epigenomic datasets have indicated that T cells drive asthma risk, which has been supported by mouse studies. However, the datasets ascertained in these integrative analyses lack airway epithelial cells. Furthermore, large-scale transcriptomic T cell studies have not identified the regulatory effects of most non-coding risk variants in asthma GWAS, indicating there could be additional cell types harboring these "missing regulatory effects". Given that airway epithelial cells are the first line of defense against rhinovirus, we hypothesized they could be mediators of genetic susceptibility to asthma. Here we integrate GWAS data with transcriptomic datasets of airway epithelial cells subject to stimuli that could induce activation states relevant to asthma. We demonstrate that epithelial cultures infected with rhinovirus significantly upregulate childhood-onset asthma-associated genes. We show that this upregulation occurs specifically in non-ciliated epithelial cells. This enrichment for genes in asthma risk loci, or 'asthma heritability enrichment' is also significant for epithelial genes upregulated with influenza infection, but not with SARS-CoV-2 infection or cytokine activation. Additionally, cells from patients with asthma showed a stronger heritability enrichment compared to cells from healthy individuals. Overall, our results suggest that rhinovirus infection is an environmental factor that interacts with genetic risk factors through non-ciliated airway epithelial cells to drive childhood-onset asthma.

Preprint↗

PubMed2026

Exploring the Effect of Whole-Genome Duplication on Salmonid LincRNA Repertoire.

Long intergenic non-coding RNAs (lincRNAs) are key epigenetic regulators of genome function, yet their evolutionary dynamics following whole-genome duplication (WGD) events remain poorly understood. Salmonids, which underwent a lineage-specific autotetraploidization (salmonid-specific WGD, ~88-100 million years ago), provide an excellent model to investigate the retention, divergence, and functional potential of recently duplicated non-coding elements. LincRNA repertoires were compared across five genome-annotated salmonids (Oncorhynchus tshawytscha, O. kisutch, O. mykiss, Salmo salar, and S. trutta) and their closest non-duplicated relative, northern pike (Esox lucius). LincRNAs represented ~5-7% of annotated genes in all salmonids except S. salar (18%). Sequence conservation was low relative to coding genes, with only 11-68 highly similar (e-value < 1 × 10-30; similarity > 70% and alignments > 100 nucleotides) putative orthologues shared between salmonids and northern pike, and 161-338 among salmonids alone. Synteny conservation was modest in lincRNAs, with lower conservation in putative orthologues (8-16%) compared to putative ohnologues (8-33%). Secondary structure conservation was associated with sequence similarity (ρ = -0.45; p = 2.2 × 10-16), and the association was stronger among WGD ohnologues than orthologues. In S. salar and O. mykiss, lincRNA putative ohnologues showed weaker expression correlations than coding genes, suggesting widespread regulatory divergence, possibly through neo- and subfunctionalisation. Conserved salmonid lincRNAs showed enriched predicted interactions with miRNAs involved in tumour suppression, brain, bone, and muscle development (e.g., miR-455, miR-365, miR124, miR-133a, miR-140, and miR-9), a finding supported by limited transcriptomic data. Although salmonid WGD expanded lincRNA repertoires, lincRNAs have undergone rapid sequence and transcriptional divergence, with limited conservation across species based on sequence similarity, chromosomal position, synteny, and secondary structure. A subset of conserved lincRNAs retains structural features and regulatory signatures consistent with roles as miRNA sponges in brain, skeletal, and muscle development and tumour suppression, potentially acting within conserved regulatory networks. These findings provide new insights into lincRNA evolution following genome duplication and highlight the need for experimental validation of their regulatory functions.

Animals↗

PubMed2004

Alcohol and gene expression in the central nervous system.

AIMS: To describe recent research focusing on the analysis of gene and protein expression relevant to understanding ethanol consumption, dependence and effects, in order to identify common themes. METHODS: A selective literature search was used to collate the relevant data. RESULTS: Over 160 genes have been individually assessed before or after ethanol administration, as well as in genetically selected lines. Techniques for studying gene expression include northern blots, differential display, real time reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization. More recently, high throughput functional genomic technology, such as DNA microarrays, has been used to examine gene expression. Recent gene expression analyses have dramatically increased the number of candidate genes (nine array papers have illuminated 600 novel gene transcripts that may contribute to alcohol abuse and alcoholism). CONCLUSIONS: Although functional genomic experiments (transcriptome analysis) have failed to identify a single alcoholism gene, they have illuminated important pathways and gene products that may contribute to the risk of alcohol abuse and alcoholism.

Alcoholism↗

PubMed2005

Transcriptome comparison of winter and spring wheat responding to low temperature.

Freezing tolerance in plants is a complex trait that occurs in many plant species during growth at low, nonfreezing temperatures, a process known as cold acclimation. This process is regulated by a multigenic system expressing broad variation in the degree of freezing tolerance among wheat cultivars. Microarray analysis is a powerful and rapid approach to gene discovery. In species such as wheat, for which large scale mutant screening and transgenic studies are not currently practical, genotype comparison by this methodology represents an essential approach to identifying key genes in the acquisition of freezing tolerance. A microarray was constructed with PCR amplified cDNA inserts from 1184 wheat expressed sequence tags (ESTs) that represent 947 genes. Gene expression during cold acclimation was compared in 2 cultivars with marked differences in freezing tolerance. Transcript levels of more than 300 genes were altered by cold. Among these, 65 genes were regulated differently between the 2 cultivars for at least 1 time point. These include genes that encode potential regulatory proteins and proteins that act in plant metabolism, including protein kinases, putative transcription factors, Ca2+ binding proteins, a Golgi localized protein, an inorganic pyrophosphatase, a cell wall associated hydrolase, and proteins involved in photosynthesis.

Acclimatization↗

PubMed2026

Emergence of cefiderocol resistance in carbapenem-resistant Escherichia coli ST167 prior to clinical use: A multifactored resistance landscape.

OBJECTIVES: Cefiderocol is a novel siderophore cephalosporin with potent activity against multidrug-resistant Gram-negative bacteria. Here, we reported the prevalence and mechanisms of cefiderocol resistance in carbapenem-resistant Escherichia coli (CREC) in China before its clinical use. METHODS: A total of 443 non-duplicate CREC isolates collected from 67 hospitals in China (2013-2021) underwent antimicrobial susceptibility testing according to CLSI guidelines. Whole-genome sequencing, transcriptomic analysis, siderophore quantification, and targeted genetic manipulation were performed to investigate the underlying resistance mechanisms. RESULTS: Among the 443 CREC isolates, 102 (23.0%) were resistant to cefiderocol, and 34 (7.6%) showed intermediate susceptibility. Multivariable logistic regression identified ST167 lineage (OR, 3.05; 95% CI, 1.12-8.29; P = 0.028), blaNDM-5 carriage (OR, 9.04; 95% CI, 2.96-27.57; P < 0.001), and cirA truncation (OR, 49.56; 95% CI, 20.33-120.79; P < 0.001) as independent factors associated with cefiderocol resistance. Among ST167 isolates, cefiderocol-resistant isolates showed increased yersiniabactin carriage and siderophore production but comparable TonB-dependent transporter expression profiles. Phylogenetic analysis revealed that cefiderocol-resistant ST167 isolates clustered into a distinct subclade enriched with resistance-associated determinants, including a recurrent FhuA P50S substitution detected in 59/64 (92.2%) resistant isolates. Functional assays showed that the P50S substitution increased cefiderocol minimum inhibitory concentration (0.032-0.125 µg/mL), particularly in an NDM-5-producing background (0.032-0.5 µg/mL). CONCLUSIONS: Cefiderocol resistance is highly prevalent among high-risk ST167 CREC isolates before the clinical introduction of cefiderocol in China, highlighting the need for continued surveillance of this epidemic lineage. Cefiderocol resistance is mediated by multiple resistance determinants, and we identify the recurrent FhuA P50S substitution as a novel contributor to reduced cefiderocol susceptibility.

Antimicrobial resistance↗

PubMed2026

Trade-off between photosynthetic promotion and nitrogen fixation suppression induced by chloroplast-targeted Mo nanoparticles in soybean.

Organelle-targeted nanomaterials offer opportunities to improve crop photosynthesis, yet their unintended effects on symbiotic nitrogen fixation remain poorly understood. Here, we developed chloroplast-targeted molybdenum nanoparticles (Chl-Mo) and compared their effects with those of ionic Mo (IonMo) and non-targeted Mo nanoparticles in soybean. Chl-Mo preferentially accumulated in chloroplasts, enhancing photosynthetic carbon assimilation, thylakoid development, PSII performance, sucrose transport, and biomass accumulation. However, this growth promotion was accompanied by suppressed nodule nitrogenase activity, reduced nif gene expression, inhibited GS/GOGAT-mediated nitrogen assimilation, and disrupted microoxic and ROS homeostasis in nodules. Integrated nodule proteomics and metabolomics showed downregulation of sucrose transport, glycolysis, pyruvate metabolism, and amino acid biosynthesis, indicating a decoupling between enhanced carbon input and nitrogen utilization. Root transcriptomics further revealed oxidative stress, impaired nitrate assimilation, and attenuated early symbiotic signaling. These findings demonstrate that chloroplast-targeted Mo delivery can enhance photosynthesis while compromising symbiotic nitrogen fixation, highlighting the need to evaluate belowground symbiotic functions when developing organelle-targeted nanotechnologies for sustainable agriculture.

Chloroplast-targeted Mo↗

PubMed2025

Targeting anti-apoptosis as a therapeutic strategy in neuroendocrine neoplasms.

BCL-2 is an anti-apoptotic protein expressed by aggressive neuroendocrine neoplasms (NENs). We report a case of a patient with a pancreatic neuroendocrine tumor (pNET) who received venetoclax, a BCL-2-targeting drug for the treatment of chronic lymphocytic leukemia. We further characterized BCL2 expression in NENs from a large multi-institutional patient cohort. Clinical data were abstracted from the records of a patient with a pNET. Next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) was performed on 636 NENs of pancreatic (P-NENs), small bowel (SB-NENs), colorectal (CR-NENs), and lung (L-NENs) origin by Caris Life Sciences. Comparisons were performed against site-matched non-NEN cancers. BCL2- or MKI67- high and low cohorts were defined based on the top and bottom quartiles of gene expression. The patient with a pNET who received venetoclax had a partial response in the primary tumor that lasted 30 months. CR-, L-, and P-NENs had significantly higher expression of BCL2 compared to non-NEN counterparts. BCL2 expression was significantly higher in MKI67-high tumors among all NEN subtypes. In P-NENs, there was a higher prevalence of RB1 mutations in BCL2-high vs BCL2-low (40 vs 4.9%, P < 0.005). Patients with BCL2-high P-NENs had significantly decreased overall survival (HR 1.94, 95% CI 1.0-3.76, P = 0.047). Immune checkpoint gene expression and T cells were enriched in BCL2-high tumors across all subtypes. In summary, we report the first known case of a pancreatic NET with response to venetoclax. BCL2 expression correlated with high MKI67 expression, worse survival, and a highly immune-enriched microenvironment.

Aged↗

PubMed2004

A bioinformatics analysis of alternative exon usage in human genes coding for extracellular matrix proteins.

Alternative splicing increases protein diversity through the generation of different mRNA molecules from the same gene. Although alternative splicing seems to be a widespread phenomenon in the human transcriptome, it is possible that different subgroups of genes present different patterns, related to their biological roles. Analysis of a subgroup may enhance common features of its members that would otherwise disappear amidst a heterogeneous population. Extracellular matrix (ECM) proteins are a good set for such analyses since they are structurally and functionally related. This family of proteins is involved in a large variety of functions, probably achieved by the combinatorial use of protein domains through exon shuffling events. To determine if ECM genes have a different pattern of alternative splicing, we compared clusters of expressed sequences of ECM to all other genes regarding features related to the most frequent type of alternative splicing, alternative exon usage (AEU), such as: the number of alternative exon-intron structures per cluster, the number of AEU events per exon-intron structure, the number of exons per event, among others. Although we did not find many differences between the two sets, we observed a higher frequency of AEU events involving entire protein domains in the ECM set, a feature that could be associated with their multi-domain nature. As other subgroups or even the ECM set in different tissues could present distinct patterns of AEU, it may be premature to conclude that alternative splicing is homogeneous among groups of related genes.

Alternative Splicing↗

PubMed2005

The mouse epididymal transcriptome: transcriptional profiling of segmental gene expression in the epididymis.

Maturation of spermatozoa, including the acquisition of motility and the ability to undergo capacitation, occurs during transit through the dynamic environment of the epididymis. The microenvironments created along the length of the epididymal tubule are essential to the molecular modifications of spermatozoa that result in fertile gametes. The secretory and resorptive processes of the epithelial cells that line this tubule generate these microenvironments. In the current study, 10 morphologically distinct segments of the mouse epididymis were identified by microdissection. We hypothesized that the changing environments of the epididymal lumen are established by differential gene expression among these segments. RNA isolated from each of the 10 segments was analyzed by microarray analysis. More than 17,000 genes are expressed in the mouse epididymis, compared with about 12,000 genes identified from whole epididymal samples. Screening a panel of normal mouse tissues identified both epididymal-selective and epididymal-specific transcripts. In addition, this study identified 2168 genes that are up-regulated or down-regulated by greater than 4-fold between at least two different segments. The expression patterns of these genes identify distinct patterns of segmental regulation. Using principal component analysis, we determined that the 10 segments form 6 different transcriptional units. These analyses elucidate the changes in gene expression along the length of the epididymis for 17,000 expressed transcripts and provide a powerful resource for the research community in future studies of the biological factors that mediate epididymal sperm maturation.

Animals↗

PubMed2002

Remodeling of DNA methylation and phenotypic and transcriptional changes in synthetic Arabidopsis allotetraploids.

The joining of different genomes in allotetraploids played a major role in plant evolution, but the molecular implications of this event are poorly understood. In synthetic allotetraploids of Arabidopsis and Cardaminopsis arenosa, we previously demonstrated the occurrence of frequent gene silencing. To explore the involvement of epigenetic phenomena, we investigated the occurrence and effects of DNA methylation changes. Changes in DNA methylation patterns were more frequent in synthetic allotetraploids than in the parents. Treatment with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase, resulted in the development of altered morphologies in the synthetic allotetraploids, but not in the parents. We profiled mRNAs in control and 5-aza-2'-deoxycytidine-treated parents and allotetraploids by amplified fragment length polymorphism-cDNA. We show that DNA demethylation induced and repressed two different transcriptomes. Our results are consistent with the hypothesis that synthetic allotetraploids have compromised mechanisms of epigenetic gene regulation.

Arabidopsis↗