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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 -
Journal of Cutaneous Pathology Nov 2023Giant cell tumor of soft tissue (GCT-ST) is a rare soft tissue neoplasm that is morphologically similar to but genetically distinct from giant cell tumor of bone. A...
BACKGROUND
Giant cell tumor of soft tissue (GCT-ST) is a rare soft tissue neoplasm that is morphologically similar to but genetically distinct from giant cell tumor of bone. A novel keratin-positive GCT-ST (KPGCT-ST) harboring HMGA2::NCOR2 fusions was recently discovered. Fewer than 30 cases have been described; herein is reported an additional seven.
METHODS
Cases diagnosed as GCT-ST were retrieved from institutional archives and consultation files. The histopathologic characteristics were assessed, and the electronic medical record was reviewed.
RESULTS
Seven tumors were identified in six women and one man with a median age of 23 years. All patients underwent excision; no recurrences or metastases were noted during a median follow-up period of 7 months. Histopathologically, the tumors were characterized by a multinodular proliferation of keratin-positive mononuclear cells with evenly admixed osteoclast-like giant cells and absent neoplastic bone. A fibrous capsule with lymphoid cuffing was frequently seen. Foamy macrophages, inflammation, hemorrhage, and hemosiderin were variably present. The HMGA2::NCOR2 fusion was detected in all cases.
CONCLUSIONS
Our findings support previously reported hypotheses that KPGCT-ST is a spectrum of the same entity as the recently described xanthogranulomatous epithelial tumor. Although follow-up data are limited, to date, KPGCT-ST appears to follow an indolent course.
Topics: Male; Humans; Female; Young Adult; Adult; Keratins; Giant Cell Tumors; Soft Tissue Neoplasms; Diagnosis, Differential; Giant Cells; Nuclear Receptor Co-Repressor 2
PubMed: 37496152
DOI: 10.1111/cup.14497 -
Clinica Chimica Acta; International... Jul 2023The sequence similarity between CYP21A2 gene and its inactive pseudogene CYP21A1P, and copy number variation (CNV) caused by unequal crossover, make it challenging to...
BACKGROUND
The sequence similarity between CYP21A2 gene and its inactive pseudogene CYP21A1P, and copy number variation (CNV) caused by unequal crossover, make it challenging to characterize the CYP21A2 gene through traditional methods. This study aimed to evaluate the clinical utility of the long-read sequencing (LRS) method in carrier screening and genetic diagnosis of congenital adrenal hyperplasia (CAH) by comparing the efficiency of the LRS method with the conventional multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing approaches in CYP21A2 analysis.
METHODS
In a retrospective study, full sequence analysis of the CYP21A2 and CYP21A1P was performed for three pedigrees through long-range locus-specific PCR followed by LRS based on the Pacific Biosciences (PacBio, California, USA) single-molecule real-time (SMRT) platform, and the results were compared with those obtained from next-generation sequencing (NGS)-based whole exome sequencing (WES) and the traditional methods of MLPA plus Sanger sequencing.
RESULTS
The LRS method successfully identified seven CYP21A2 variants, including three single nucleotide variants (NM_000500.9:c.1451G > C p.(Arg484Pro), c.293-13A/C > G (IVS2-13A/C > G), c.518 T > A p.(Ile173Asn)), one 111-bp polynucleotide insertion, one set of 3'URT variants (NM_000500.9:c.*368 T > C, c.*390A > G, c.*440C > T, c.*443 T > C) and two types of chimeric genes and straightforwardly depicted the inheritance patterns of these variants within families. Moreover, the LRS method enabled us to determine the cis-trans configuration of multiple variants in one assay, without the need to analyze additional family samples. Compared with traditional methods, this LRS method can achieve a precise, comprehensive and intuitive result in the genetic diagnosis of 21-hydroxylase deficiency (21-OHD).
CONCLUSION
The LRS method is comprehensive in CYP21A2 analysis and intuitive in result presentation, which holds substantial promise in clinical application as a crucial tool for carrier screening and genetic diagnosis of CAH.
Topics: Humans; Adrenal Hyperplasia, Congenital; Steroid 21-Hydroxylase; DNA Copy Number Variations; Retrospective Studies; Multiplex Polymerase Chain Reaction; High-Throughput Nucleotide Sequencing; Mutation
PubMed: 37276943
DOI: 10.1016/j.cca.2023.117419 -
Proceedings of the National Academy of... Apr 2024Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific...
Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4 T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as . Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including , in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.
Topics: Animals; Th17 Cells; Histone Deacetylases; Cell Differentiation; Mice; Colitis; Transcription, Genetic; Transcription Factors; Nuclear Receptor Co-Repressor 2; Interleukin-17; Gene Expression Regulation; Mice, Inbred C57BL; Humans; Repressor Proteins; Interleukin-2; Nuclear Receptor Co-Repressor 1
PubMed: 38657041
DOI: 10.1073/pnas.2312111121 -
Proceedings of the National Academy of... Feb 2024Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms...
Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRT mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.
Topics: Humans; Female; Male; Animals; Mice; DNA-Binding Proteins; Repressor Proteins; Co-Repressor Proteins; Nuclear Receptor Co-Repressor 2; Tretinoin; Contraception; Nuclear Receptor Co-Repressor 1
PubMed: 38377195
DOI: 10.1073/pnas.2320129121 -
The American Journal of Surgical... Jul 2023Giant cell tumors (GCTs) with high mobility group AT-Hook 2 ( HMGA2 )::nuclear receptor corepressor 2 ( NCOR2 ) fusion are rare mesenchymal tumors of controversial...
Giant cell tumors (GCTs) with high mobility group AT-Hook 2 ( HMGA2 )::nuclear receptor corepressor 2 ( NCOR2 ) fusion are rare mesenchymal tumors of controversial nosology, which have been anecdotally reported to respond to CSFR1 inhibitors. Here, we performed a comprehensive study of 6 GCTs with HMGA2::NCOR2 fusion and explored their relationship with other giant cell-rich neoplasms. Tumors occurred in 4 females and 2 males ranging in age from 17 to 32 years old (median 24). Three lesions originated in subcutaneous soft tissue and 3 in bone. Tumor size ranged from 20 to 33 mm (median 27 mm). The lesions had a nodular/multinodular architecture and were composed of sheets of mononuclear "histiocytoid" cells with uniform nuclei intermingled with multinucleated giant cells. Mitotic activity was low and nuclear atypia and metaplastic bone were absent. Variable findings included necrosis, cystic degeneration, lymphocytic infiltrate (sometimes forming nodules), and xanthogranulomatous inflammation. On immunohistochemistry, all cases focally expressed pan-keratin and were negative with SATB2 and H3.3G34W. Whole RNA-sequencing was performed in all cases of GCT with HMGA2::NCOR2 fusion and a subset of giant cell-rich tumors (tenosynovial-GCT, n = 19 and "wild-type" GCT of soft tissue, n = 9). Hierarchical clustering of RNA-sequencing data showed that GCT with HMGA2::NCOR2 fusion formed a single cluster, independent of the other 2 entities. Methylome profiling showed similar results, but the distinction from "wild-type" GCT of soft tissue was less flagrant. Gene expression analysis showed similar levels of expression of the CSF1/CSFR1 axis between GCT with HMGA2::NCOR2 fusion and tenosynovial-GCT, supporting their potential sensitivity to CSFR1 inhibitors. Clinical follow-up was available for 5 patients (range: 10 to 64 mo; median 32 mo). Three patients (60%) experienced local recurrences, whereas none had distant metastases or died of disease. Overall, our study confirms and expands previous knowledge on GCT with HMGA2::NCOR2 fusion and supports its inclusion as an independent entity.
Topics: Male; Female; Humans; Adolescent; Young Adult; Adult; Biomarkers, Tumor; Giant Cell Tumors; Immunohistochemistry; Bone and Bones; Epigenesis, Genetic; Nuclear Receptor Co-Repressor 2
PubMed: 37170907
DOI: 10.1097/PAS.0000000000002051