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Communications Biology Oct 2023Talaromyces marneffei (T. marneffei) immune escape is essential in the pathogenesis of talaromycosis. It is currently known that T. marneffei achieves immune escape...
Talaromyces marneffei (T. marneffei) immune escape is essential in the pathogenesis of talaromycosis. It is currently known that T. marneffei achieves immune escape through various strategies. However, the role of cellular alternative splicing (AS) in immune escape remains unclear. Here, we depict the AS landscape in macrophages upon T. marneffei infection via high-throughput RNA sequencing and detect a truncated protein of NCOR2 / SMRT, named NCOR2-013, which is significantly upregulated after T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1 / TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Furthermore, we identify TUT1 as the AS regulator that regulates NCOR2-013 production and promotes T. marneffei immune evasion. Collectively, these findings indicate that T. marneffei escapes macrophage killing through TUT1-mediated alternative splicing of NCOR2 / SMRT, providing insight into the molecular mechanisms of T. marneffei immune evasion and potential targets for talaromycosis therapy.
Topics: Humans; Alternative Splicing; Macrophages; Inflammation
PubMed: 37845378
DOI: 10.1038/s42003-023-05409-6 -
IBRO Neuroscience Reports Dec 2023Rett Syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants in the gene. While the majority of RTT-causing variants are clustered in the...
Rett Syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants in the gene. While the majority of RTT-causing variants are clustered in the methyl-CpG binding domain and NCoR/SMRT interaction domain, we report a female patient with a functionally uncharacterized variant in the C-terminal domain, c.1030C>T (R344W). We functionally characterized MECP2-R344W in terms of protein stability, NCoR/SMRT complex interaction, and protein nuclear localization in vitro. MECP2-R344W cells showed an increased protein degradation rate without significant change in NCoR/SMRT complex interaction and nuclear localization pattern, suggesting that enhanced MECP2 degradation is sufficient to cause a Rett Syndrome-like phenotype. This study highlights the pathogenicity of the C-terminal domain in Rett Syndrome, and demonstrates the potential of targeting MECP2 protein stability as a therapeutic approach.
PubMed: 37822516
DOI: 10.1016/j.ibneur.2023.09.007 -
Frontiers in Microbiology 2023Globally, due to widespread dispersion, intraspecific diversity, and crucial ecological components of halophilic ecosystems, bacteria is considered one of the key...
Globally, due to widespread dispersion, intraspecific diversity, and crucial ecological components of halophilic ecosystems, bacteria is considered one of the key models for ecological, adaptative, and biotechnological applications research in saline environments. With this aim, the present study was to enlighten the plant growth-promoting features and investigate the systematic genome of a halophilic bacteria, ASH15, through single-molecule real-time (SMRT) sequencing technology. Results showed that strain ASH15 could survive in high salinity up to 25% (w/v) NaCl concentration and express plant growth-promoting traits such as nitrogen fixation, plant growth hormones, and hydrolytic enzymes, which sustain salt stress. The results of pot experiment revealed that strain ASH15 significantly enhanced sugarcane plant growth (root shoot length and weight) under salt stress conditions. Moreover, the sequencing analysis of the strain ASH15 genome exhibited that this strain contained a circular chromosome of 3,832,903 bp with an average G+C content of 37.54%: 3721 predicted protein-coding sequences (CDSs), 24 rRNA genes, and 62 tRNA genes. Genome analysis revealed that the genes related to the synthesis and transport of compatible solutes (glycine, betaine, ectoine, hydroxyectoine, and glutamate) confirm salt stress as well as heavy metal resistance. Furthermore, functional annotation showed that the strain ASH15 encodes genes for root colonization, biofilm formation, phytohormone IAA production, nitrogen fixation, phosphate metabolism, and siderophore production, which are beneficial for plant growth promotion. Strain ASH15 also has a gene resistance to antibiotics and pathogens. In addition, analysis also revealed that the genome strain ASH15 has insertion sequences and CRISPRs, which suggest its ability to acquire new genes through horizontal gene transfer and acquire immunity to the attack of viruses. This work provides knowledge of the mechanism through which ASH15 tolerates salt stress. Deep genome analysis, identified MVA pathway involved in biosynthesis of isoprenoids, more precisely "Squalene." Squalene has various applications, such as an antioxidant, anti-cancer agent, anti-aging agent, hemopreventive agent, anti-bacterial agent, adjuvant for vaccines and drug carriers, and detoxifier. Our findings indicated that strain ASH15 has enormous potential in industries such as in agriculture, pharmaceuticals, cosmetics, and food.
PubMed: 37808307
DOI: 10.3389/fmicb.2023.1229955 -
Biology Aug 2023The peanut worm () is an important intertidal species worldwide. Species living in the same aquaculture area might suffer different environmental impacts. To increase...
The peanut worm () is an important intertidal species worldwide. Species living in the same aquaculture area might suffer different environmental impacts. To increase knowledge of the molecular mechanisms underlying the response to environmental fluctuations, we performed a transcriptome analysis of from different intertidal zones using a combination of the SMRT platform and the Illumina sequencing platform. (1) A total of 105,259 unigenes were assembled, and 23,063 unigenes were perfectly annotated. The results of the PacBio Iso-Seq and IIIumina RNA-Seq enriched the genetic database of . (2) A total of 830 DEGs were detected in from the different groups. In particular, 33 DEGs had differential expression in the top nine KEGG pathways related to pathogens, protein synthesis, and cellular immune response and signaling. The results indicate that from different zones experience different environmental stresses. (3) Several DEGs (, , , etc.) in pathways related to pathogens (influenza A, legionellosis, measles, and toxoplasmosis) had higher expression in groups M and L. was clearly enriched in most of the pathways, followed by . The results show that the peanut worms from the M and L tidal flats might have suffered more severe environmental conditions. (4) Some DEGs (, and ) were upregulated in peanut worms from the H tidal flat, and these DEGs were mainly involved in the MAPK signaling pathway. These results indicate that the MAPK pathway may play a vital role in the immune response of the peanut worm to the effects of different intertidal flats. This study provides a valuable starting point for further studies to elucidate the molecular basis of the response to different environmental stresses in .
PubMed: 37759582
DOI: 10.3390/biology12091182 -
European Thyroid Journal Oct 2023Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone...
Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C ) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified.
Topics: Animals; Mice; Co-Repressor Proteins; Receptors, Thyroid Hormone; RNA, Messenger; Thyroid Hormones; Transducin
PubMed: 37458724
DOI: 10.1530/ETJ-23-0077 -
EMBO Molecular Medicine Aug 2023Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)-positive breast cancers....
Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)-positive breast cancers. However, their efficacy is limited by intrinsic and acquired resistance to treatment, and there is currently no predictive marker of response to these anti-estrogens to guide treatment decision. Here, using two independent cohorts of breast cancer patients, we identified nuclear PRMT5 expression as an independent predictive marker of sensitivity to tamoxifen. Mechanistically, we discovered that tamoxifen stimulates ERα methylation by PRMT5, a key event for its binding to corepressors such as SMRT and HDAC1, participating in the inhibition of the transcriptional activity of ERα. Although PRMT5 is mainly localized in the cytoplasm of tumor cells, our analyses show that tamoxifen triggers its nuclear translocation in tamoxifen-sensitive tumors but not in resistant ones. Hence, we unveil a biomarker of sensitivity to tamoxifen in ERα-positive breast tumors that could be used to enhance the response of breast cancer patients to endocrine therapy, by fostering its nuclear expression.
Topics: Humans; Female; Tamoxifen; Breast Neoplasms; Estrogen Receptor alpha; Signal Transduction; Biomarkers; Drug Resistance, Neoplasm; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Antineoplastic Agents, Hormonal; Protein-Arginine N-Methyltransferases
PubMed: 37458145
DOI: 10.15252/emmm.202217248 -
Development (Cambridge, England) Aug 2023The histone deacetylase HDAC3 is associated with the NCoR/SMRT co-repressor complex, and its canonical function is in transcriptional repression, but it can also...
The histone deacetylase HDAC3 is associated with the NCoR/SMRT co-repressor complex, and its canonical function is in transcriptional repression, but it can also activate transcription. Here, we show that the repressor and activator functions of HDAC3 can be genetically separated in Drosophila. A lysine substitution in the N terminus (K26A) disrupts its catalytic activity and activator function, whereas a combination of substitutions (HEBI) abrogating the interaction with SMRTER enhances repressor activity beyond wild type in the early embryo. We conclude that the crucial functions of HDAC3 in embryo development involve catalytic-dependent gene activation and non-enzymatic repression by several mechanisms, including tethering of loci to the nuclear periphery.
Topics: Animals; Drosophila; Gene Expression Regulation; Repressor Proteins; Drosophila Proteins; Histone Deacetylases
PubMed: 37455638
DOI: 10.1242/dev.201548 -
MBio Aug 2023High-risk human papillomaviruses (PV) account for approximately 600,000 new cancers per year. The early protein E8^E2 is a conserved repressor of PV replication, whereas...
Mus musculus papillomavirus 1 E8^E2 represses expression of late protein E4 in basal-like keratinocytes via NCoR/SMRT-HDAC3 co-repressor complexes to enable wart formation .
High-risk human papillomaviruses (PV) account for approximately 600,000 new cancers per year. The early protein E8^E2 is a conserved repressor of PV replication, whereas E4 is a late protein that arrests cells in G2 and collapses keratin filaments to facilitate virion release. While inactivation of the Mus musculus PV1 (MmuPV1) start codon (E8-) increases viral gene expression, surprisingly, it prevents wart formation in FoxN1 mice. To understand this surprising phenotype, the impact of additional E8^E2 mutations was characterized in tissue culture and mice. MmuPV1 and HPV E8^E2 similarly interact with cellular NCoR/SMRT-HDAC3 co-repressor complexes. Disruption of the splice donor sequence used to generate the transcript or E8^E2 mutants (mt) with impaired binding to NCoR/SMRT-HDAC3 activates MmuPV1 transcription in murine keratinocytes. These MmuPV1 E8^E2 mt genomes also fail to induce warts in mice. The phenotype of E8^E2 mt genomes in undifferentiated cells resembles productive PV replication in differentiated keratinocytes. Consistent with this, E8^E2 mt genomes induced aberrant E4 expression in undifferentiated keratinocytes. In line with observations for HPV, MmuPV1 E4-positive cells displayed a shift to the G2 phase of the cell cycle. In summary, we propose that in order to enable both expansion of infected cells and wart formation , MmuPV1 E8^E2 inhibits E4 protein expression in the basal keratinocytes that would otherwise undergo E4-mediated cell cycle arrest. IMPORTANCE Human papillomaviruses (PVs) initiate productive replication, which is characterized by genome amplification and expression of E4 protein strictly within suprabasal, differentiated keratinocytes. Mus musculus PV1 mutants that disrupt splicing of the E8^E2 transcript or abolish the interaction of E8^E2 with cellular NCoR/SMRT-HDAC3 co-repressor complexes display increased gene expression in tissue culture but are unable to form warts . This confirms that the repressor activity of E8^E2 is required for tumor formation and genetically defines a conserved E8 interaction domain. E8^E2 prevents expression of E4 protein in basal-like, undifferentiated keratinocytes and thereby their arrest in G2 phase. Since binding of E8^E2 to NCoR/SMRT-HDAC3 co-repressor is required to enable expansion of infected cells in the basal layer and wart formation , this interaction represents a novel, conserved, and potentially druggable target.
PubMed: 37382436
DOI: 10.1128/mbio.00696-23 -
Genes Jun 2023Savalani hairtail is a widely distributed fish along the Indo-Western Pacific coast, and contributes substantially to trichiurid fishery resources worldwide. In this...
Savalani hairtail is a widely distributed fish along the Indo-Western Pacific coast, and contributes substantially to trichiurid fishery resources worldwide. In this study, the first chromosome-level genome assembly of was obtained by PacBio SMRT-Seq, Illumina HiSeq, and Hi-C technologies. The final assembled genome was 790.02 Mb with contig N50 and scaffold N50 values of 19.01 Mb and 32.77 Mb, respectively. The assembled sequences were anchored to 24 chromosomes by using Hi-C data. Combined with RNA sequencing data, 23,625 protein-coding genes were predicted, of which 96.0% were successfully annotated. In total, 67 gene family expansions and 93 gene family contractions were detected in the genome. Additionally, 1825 positively selected genes were identified. Based on a comparative genomic analysis, we screened a number of candidate genes associated with the specific morphology, behaviour-related immune system, and DNA repair mechanisms in . Our results preliminarily revealed mechanisms underlying the special morphological and behavioural characteristics of from a genomic perspective. Furthermore, this study provides valuable reference data for subsequent molecular ecology studies of and whole-genome analyses of other trichiurid fishes.
Topics: Animals; Perciformes; Chromosomes; Genome; Genomics; Evolution, Molecular; Multigene Family; Phylogeny
PubMed: 37372448
DOI: 10.3390/genes14061268 -
BMC Genomics Jun 2023Oriental river prawn (Macrobrachium nipponense) is one of the most dominant species in shrimp farming in China, which is a rich source of protein and contributes to a...
BACKGROUND
Oriental river prawn (Macrobrachium nipponense) is one of the most dominant species in shrimp farming in China, which is a rich source of protein and contributes to a significant impact on the quality of human life. Thus, more complete and accurate annotation of gene models are important for the breeding research of oriental river prawn.
RESULTS
A full-length transcriptome of oriental river prawn muscle was obtained using the PacBio Sequel platform. Then, 37.99 Gb of subreads were sequenced, including 584,498 circular consensus sequences, among which 512,216 were full length non-chimeric sequences. After Illumina-based correction of long PacBio reads, 6,599 error-corrected isoforms were identified. Transcriptome structural analysis revealed 2,263 and 2,555 alternative splicing (AS) events and alternative polyadenylation (APA) sites, respectively. In total, 620 novel genes (NGs), 197 putative transcription factors (TFs), and 291 novel long non-coding RNAs (lncRNAs) were identified.
CONCLUSIONS
In summary, this study offers novel insights into the transcriptome complexity and diversity of this prawn species, and provides valuable information for understanding the genomic structure and improving the draft genome annotation of oriental river prawn.
Topics: Animals; Humans; Palaemonidae; Gene Expression Profiling; Transcriptome; Alternative Splicing; Protein Isoforms
PubMed: 37340366
DOI: 10.1186/s12864-023-09442-x