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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 -
Microorganisms Sep 2023When compared with bacteria, relatively little is known about the restriction-modification (RM) systems of archaea, particularly those in taxa outside of the...
When compared with bacteria, relatively little is known about the restriction-modification (RM) systems of archaea, particularly those in taxa outside of the haloarchaea. To improve our understanding of archaeal RM systems, we surveyed REBASE, the restriction enzyme database, to catalog what is known about the genes and activities present in the 519 completely sequenced archaeal genomes currently deposited there. For 49 (9.4%) of these genomes, we also have methylome data from Single-Molecule Real-Time (SMRT) sequencing that reveal the target recognition sites of the active mA and mC DNA methyltransferases (MTases). The gene-finding pipeline employed by REBASE is trained primarily on bacterial examples and so will look for similar genes in archaea. Nonetheless, the organizational structure and protein sequence of RM systems from archaea are highly similar to those of bacteria, with both groups acquiring systems from a shared genetic pool through horizontal gene transfer. As in bacteria, we observe numerous examples of "persistent" DNA MTases conserved within archaeal taxa at different levels. We experimentally validated two homologous members of one of the largest "persistent" MTase groups, revealing that methylation of C(mC)WGG sites may play a key epigenetic role in Crenarchaea. Throughout the archaea, genes encoding mA, mC, and mC DNA MTases, respectively, occur in approximately the ratio 4:2:1.
PubMed: 37894082
DOI: 10.3390/microorganisms11102424 -
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 -
Biomedicine & Pharmacotherapy =... Apr 2024Prostate cancer (PCa) is witnessing a concerning rise in incidence annually, with the androgen receptor (AR) emerging as a pivotal contributor to its growth and... (Review)
Review
Prostate cancer (PCa) is witnessing a concerning rise in incidence annually, with the androgen receptor (AR) emerging as a pivotal contributor to its growth and progression. Mounting evidence underscores the AR's ability to recruit cofactors, influencing downstream gene transcription and thereby fueling the proliferation and metastasis of PCa cells. Although, clinical strategies involving AR antagonists provide some relief, managing castration resistant prostate cancer (CRPC) remains a formidable challenge. Thus, the need of the hour lies in unearthing new drugs or therapeutic targets to effectively combat PCa. This review encapsulates the pivotal roles played by coactivators and corepressors of AR, notably androgen receptor-associated protein (ARA) and steroid receptor Coactivators (SRC) in PCa. Our data unveils how these cofactors intricately modulate histone modifications, cell cycling, SUMOylation, and apoptosis through their interactions with AR. Among the array of cofactors scrutinised, such as ARA70β, ARA24, ARA160, ARA55, ARA54, PIAS1, PIAS3, SRC1, SRC2, SRC3, PCAF, p300/CBP, MED1, and CARM1, several exhibit upregulation in PCa. Conversely, other cofactors like ARA70α, PIASy, and NCoR/SMRT demonstrate downregulation. This duality underscores the complexity of AR cofactor dynamics in PCa. Based on our findings, we propose that manipulating cofactor regulation to modulate AR function holds promise as a novel therapeutic avenue against advanced PCa. This paradigm shift offers renewed hope in the quest for effective treatments in the face of CRPC's formidable challenges.
Topics: Male; Humans; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Prostatic Neoplasms; Cell Line, Tumor; Molecular Chaperones; Protein Inhibitors of Activated STAT
PubMed: 38417290
DOI: 10.1016/j.biopha.2024.116338 -
RNA (New York, N.Y.) Feb 2024XIST noncoding RNA promotes the initiation of X chromosome silencing by recruiting the protein SPEN to one X chromosome in female mammals. The SPEN protein is also...
XIST noncoding RNA promotes the initiation of X chromosome silencing by recruiting the protein SPEN to one X chromosome in female mammals. The SPEN protein is also called SHARP (SMRT and HDAC-associated repressor protein) and MINT (Msx-2 interacting nuclear target) in humans. SPEN recruits N-CoR2 and HDAC3 to initiate histone deacetylation on the X chromosome, leading to the formation of repressive chromatin marks and silencing gene expression. We dissected the contributions of different RNA and protein regions to the formation of a human XIST-SPEN complex in vitro and identified novel sequence and structure determinants that may contribute to X chromosome silencing initiation. Binding of SPEN to XIST RNA requires RRM 4 of the protein, in contrast to the requirement of RRM 3 and RRM 4 for specific binding to SRA RNA. Measurements of SPEN binding to full-length, dimeric, trimeric, or other truncated versions of the A-repeat region revealed that high-affinity binding of XIST to SPEN in vitro requires a minimum of four A-repeat segments. SPEN binding to XIST A-repeat RNA changes the accessibility of the RNA at specific nucleotide sequences, as indicated by changes in RNA reactivity through chemical structure probing. Based on computational modeling, we found that inter-repeat duplexes formed by multiple A-repeats can present an unpaired adenosine in the context of a double-stranded region of RNA. The presence of this specific combination of sequence and structural motifs correlates with high-affinity SPEN binding in vitro. These data provide new information on the molecular basis of the XIST and SPEN interaction.
Topics: Female; Humans; Chromatin; DNA-Binding Proteins; Gene Silencing; RNA, Long Noncoding; RNA, Untranslated; RNA-Binding Proteins; X Chromosome; X Chromosome Inactivation
PubMed: 38164599
DOI: 10.1261/rna.079713.123 -
BMC Plant Biology Nov 2023Trachycarpus fortunei is a plant with significant economic and ornamental value. Both male and female flowers of T. fortunei originate as bisexual flowers, and selective...
BACKGROUND
Trachycarpus fortunei is a plant with significant economic and ornamental value. Both male and female flowers of T. fortunei originate as bisexual flowers, and selective abortion occurs during floral development. However, the regulatory mechanisms underlying this process remain unclear in T. fortunei. In this study, transcriptome sequencing with Illumina and Pacific BioSciences (PacBio) single-molecule real-time (SMRT) platforms were used to investigate gene expression differences between male and female T. fortunei plants.
RESULTS
A total of 833,137 full-length non-chimeric (FLNC) reads were obtained, and 726,846 high-quality full-length transcripts were identified. A total of 159 genes were differentially expressed between male and female flowers at all development stages. Some of the differentially expressed genes (DEGs) showed male bias, including serine/threonine-protein kinase (STPK), THUMP1 homolog and other genes. Through single-nucleotide polymorphisms(SNPs) identification, 28 genes were considered as potential sex-associated SNPs. Time-Ordered Gene Co-expression Network (TO-GCN) analysis revealed that MADS2 and MADS26 may play important roles in the development of female and male flowers T. fortune plants, respectively.
CONCLUSIONS
These findings provide a genetic basis for flower development and differentiation in T. fortunei, and improve our understanding of the mechanisms underlying sexual differentiation in T. fortunei.
Topics: Transcriptome; Gene Expression Regulation, Plant; Gene Expression Profiling; Flowers; High-Throughput Nucleotide Sequencing; Arecaceae
PubMed: 37919651
DOI: 10.1186/s12870-023-04551-x -
Animals : An Open Access Journal From... Nov 2023The Chinese soft-shelled turtle (), an economically important aquatic species in China, displays considerable sexual dimorphism: the male is larger and, thus, more...
The Chinese soft-shelled turtle (), an economically important aquatic species in China, displays considerable sexual dimorphism: the male is larger and, thus, more popular in the market. In this study, we obtained the full-length (FL) transcriptome data of by using Pacific Biosciences (PacBio)'s isoform sequencing and analyzed the transcriptome structure. In total, 1,536,849 high-quality FL transcripts were obtained through single-molecule real-time (SMRT) sequencing, which were then corrected using Illumina sequencing data. Next, 89,666 nonredundant FL transcripts were generated after mapping to the reference genome of ; 291 fusion genes and 17,366 novel isoforms were successfully annotated using data from the nonredundant protein sequence database (NR), eukaryotic orthology groups (KOG), the Gene Ontology (GO) project, and the KEGG Orthology (KO) database. Additionally, 19,324 alternative polyadenylation sites, 101,625 alternative splicing events, 12,392 long noncoding RNAs, and 5916 transcription factors were identified. , , and 17- were identified as female-biased genes, while and held a higher expression level in males than females. In summary, we found differences between male and female individuals in AS, lncRNA, genes, and transcripts, which relate to the Wnt pathway, oocyte meiosis, and the TGF-β pathway. Female-biased genes such as , and and male-biased genes such as and played important roles in the sex determination of . FL transcripts are a precious resource for characterizing the transcriptome of , laying the foundation for further research on the sex-determination mechanisms of .
PubMed: 38067055
DOI: 10.3390/ani13233704 -
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 -
Scientific Data Jun 2024Camellia crapnelliana Tutch., belonging to the Theaceae family, is an excellent landscape tree species with high ornamental values. It is particularly an important woody...
Camellia crapnelliana Tutch., belonging to the Theaceae family, is an excellent landscape tree species with high ornamental values. It is particularly an important woody oil-bearing plant species with high ecological, economic, and medicinal values. Here, we first report the chromosome-scale reference genome of C. crapnelliana with integrated technologies of SMRT, Hi-C and Illumina sequencing platforms. The genome assembly had a total length of ~2.94 Gb with contig N50 of ~67.5 Mb, and ~96.34% of contigs were assigned to 15 chromosomes. In total, we predicted 37,390 protein-coding genes, ~99.00% of which could be functionally annotated. The chromosome-scale genome of C. crapnelliana will become valuable resources for understanding the genetic basis of the fatty acid biosynthesis, and greatly facilitate the exploration and conservation of C. crapnelliana.
Topics: Camellia; Genome, Plant; Chromosomes, Plant; High-Throughput Nucleotide Sequencing
PubMed: 38849406
DOI: 10.1038/s41597-024-03459-x