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Cell Jul 2020The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that...
The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Chromatin; Germinal Center; Histone Deacetylases; Humans; Immunologic Memory; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis, Site-Directed; Nuclear Proteins; Nuclear Receptor Co-Repressor 2; Precursor Cells, B-Lymphoid; Protein Binding; Proto-Oncogene Proteins c-bcl-6; RNA Interference; RNA, Small Interfering; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; Transcription, Genetic
PubMed: 32619424
DOI: 10.1016/j.cell.2020.05.049 -
Nature Cancer Jun 2022Resistance to antitumor treatment contributes to patient mortality. Functional proteomic screening of organoids derived from chemotherapy-treated patients with breast...
Resistance to antitumor treatment contributes to patient mortality. Functional proteomic screening of organoids derived from chemotherapy-treated patients with breast cancer identified nuclear receptor corepressor 2 (NCOR2) histone deacetylase as an inhibitor of cytotoxic stress response and antitumor immunity. High NCOR2 in the tumors of patients with breast cancer predicted chemotherapy refractoriness, tumor recurrence and poor prognosis. Molecular studies revealed that NCOR2 inhibits antitumor treatment by regulating histone deacetylase 3 (HDAC3) to repress interferon regulatory factor 1 (IRF-1)-dependent gene expression and interferon (IFN) signaling. Reducing NCOR2 or impeding its epigenetic activity by modifying its interaction with HDAC3 enhanced chemotherapy responsiveness and restored antitumor immunity. An adeno-associated viral NCOR2-HDAC3 competitor potentiated chemotherapy and immune checkpoint therapy in culture and in vivo by permitting transcription of IRF-1-regulated proapoptosis and inflammatory genes to increase IFN-γ signaling. The findings illustrate the utility of patient-derived organoids for drug discovery and suggest that targeting stress and inflammatory-repressor complexes such as NCOR2-HDAC3 could overcome treatment resistance and improve the outcome of patients with cancer.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Early Detection of Cancer; Female; Humans; Neoplasm Recurrence, Local; Nuclear Receptor Co-Repressor 2; Organoids; Proteomics
PubMed: 35618935
DOI: 10.1038/s43018-022-00375-0 -
Cell Host & Microbe Jul 2021Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T. gondii effector TgIST blocks the transcription of...
Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T. gondii effector TgIST blocks the transcription of interferon-stimulated genes to reduce immune defense. Interferons upregulate numerous genes, including protein kinase R (PKR), which induce necrosome formation to activate mixed-lineage-kinase-domain-like (MLKL) pseudokinase and induce necroptosis. Whether these interferon functions are targeted by Toxoplasma is unknown. Here, we examine secreted effectors that localize to the host cell nucleus and find that the chronic bradyzoite stage secretes effector TgNSM that targets the NCoR/SMRT complex, a repressor for various transcription factors, to inhibit interferon-regulated genes involved in cell death. TgNSM acts with TgIST to block IFN-driven expression of PKR and MLKL, thus preventing host cell necroptotic death and protecting the parasite's intracellular niche. The mechanism of action of TgNSM uncovers a role of NCoR/SMRT in necroptosis, assuring survival of intracellular cysts and chronic infection.
Topics: HeLa Cells; Host-Parasite Interactions; Humans; Necroptosis; Nuclear Receptor Co-Repressor 2; Protein Kinases; Protozoan Proteins; Toxoplasma; Toxoplasmosis; eIF-2 Kinase
PubMed: 34043960
DOI: 10.1016/j.chom.2021.04.016 -
Neuropharmacology May 2014Epigenetic modifications are a central mechanism for regulating chromatin structure and gene expression in the brain. A wide array of histone- and DNA-modifying enzymes... (Review)
Review
Epigenetic modifications are a central mechanism for regulating chromatin structure and gene expression in the brain. A wide array of histone- and DNA-modifying enzymes have been identified as critical regulators of neuronal function, memory formation, and as causative agents in neurodevelopmental and neuropsychiatric disorders. Chromatin modifying enzymes are frequently incorporated into large multi-protein co-activator and co-repressor complexes, where the activity of multiple enzymes is both spatially and temporally coordinated. In this review, we discuss negative regulation of gene expression by co-repressor complexes, and the role of co-repressors and their binding partners in neuronal function, memory, and disease.
Topics: Animals; Brain; Chromatin Assembly and Disassembly; Co-Repressor Proteins; Epigenetic Repression; Gene Expression Regulation; Humans; Memory; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Models, Biological; Nerve Tissue Proteins; Nervous System Diseases; Neurons; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2; Repressor Proteins; Sin3 Histone Deacetylase and Corepressor Complex; Transcription, Genetic
PubMed: 24440532
DOI: 10.1016/j.neuropharm.2014.01.003 -
Proceedings of the National Academy of... Aug 2022Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold...
Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the functions of NCoR1/2 in BAT have not been established. Here we report that as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing data revealed that NCoR1/2 directly regulate , which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances stimulation of HDAC3 activity in the control of thermogenesis.
Topics: Adipose Tissue, Brown; Animals; Histone Deacetylases; Inflammation; Mice; Mice, Knockout; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2; Receptors, Retinoic Acid; Thermogenesis; Uncoupling Protein 1
PubMed: 35939699
DOI: 10.1073/pnas.2205276119 -
PloS One 2022Tokay Gecko (Gekko gecko) is a rare and endangered medicinal animal in China. Its dry body has been used as an anti-asthmatic agent for two thousand years. To date, the...
Tokay Gecko (Gekko gecko) is a rare and endangered medicinal animal in China. Its dry body has been used as an anti-asthmatic agent for two thousand years. To date, the genome and transcriptome of this species remain poorly understood. Here, we adopted single molecule real-time (SMRT) sequencing to obtain full-length transcriptome data and characterized the transcriptome structure. We identified 882,273 circular consensus (CCS) reads, including 746,317 full-length nonchimeric (FLNC) reads. The transcript cluster analysis revealed 212,964 consensus sequences, including 203,994 high-quality isoforms. In total, 111,372 of 117,888 transcripts were successfully annotated against eight databases (Nr, eggNOG, Swiss-Prot, GO, COG, KOG, Pfam and KEGG). Furthermore, 23,877 alternative splicing events, 169,128 simple sequence repeats (SSRs), 10,437 lncRNAs and 7,932 transcription factors were predicted across all transcripts. To our knowledge, this report is the first to document the G. gecko transcriptome using SMRT sequencing. The full-length transcript data might accelerate transcriptome research and lay the foundation for further research on G. gecko.
Topics: Alternative Splicing; Animals; Genome; High-Throughput Nucleotide Sequencing; Lizards; Microsatellite Repeats; Protein Isoforms; RNA; RNA, Long Noncoding; Sequence Analysis, RNA; Transcription Factors; Transcriptome
PubMed: 35213661
DOI: 10.1371/journal.pone.0264499 -
Genes & Development Apr 2013Epigenetic regulation of gene expression is strongly influenced by the accessibility of nucleosomal DNA or the state of chromatin compaction. In this context,... (Review)
Review
Epigenetic regulation of gene expression is strongly influenced by the accessibility of nucleosomal DNA or the state of chromatin compaction. In this context, coregulators, including both coactivators and corepressors, are pivotal intermediates that bridge chromatin-modifying enzymes and transcription factors. NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) are among the best-characterized corepressors from a molecular point of view. These coregulators have conserved orthologs in lower organisms, which underscores their functional importance. Here we summarize the results from recent in vivo studies that reveal the wide-ranging roles of NCoR1 and SMRT in developmental as well as homeostatic processes, including metabolism, inflammation, and circadian rhythms. We also discuss the potential implications of NCoR1 and SMRT regulation of pathways ranging from genomic stability and carcinogenesis to metabolic diseases such as type 2 diabetes.
Topics: Animals; Gene Expression Regulation; Homeostasis; Humans; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2
PubMed: 23630073
DOI: 10.1101/gad.214023.113 -
Frontiers in Immunology 2022Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance...
Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4 and CD8 T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, and were down-regulated in () depleted cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT depleted cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8 T-cell frequency, respectively. We also depicted decreased expression in Rheumatoid Arthritis, a Th1/Th17 disease.
Topics: Animals; CD8-Positive T-Lymphocytes; Cytokines; Dendritic Cells; Interleukin-10; Interleukin-12; Interleukin-23; Interleukin-6; Mice; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2; STAT3 Transcription Factor; TOR Serine-Threonine Kinases
PubMed: 36238311
DOI: 10.3389/fimmu.2022.910705 -
Biochimie Oct 2012Adiponectin has been receiving a great deal of attention due to its potential therapeutic use for metabolic and cardiovascular disorders. Adiponectin expression levels... (Review)
Review
Adiponectin has been receiving a great deal of attention due to its potential therapeutic use for metabolic and cardiovascular disorders. Adiponectin expression levels and multimerization are down-regulated in obesity and up-regulated by insulin sensitizers such as thiazolidinediones (TZDs), metformin, sulfonylurea and resveratrol (RSV). The precise mechanisms underlying adiponectin up- and down-regulation remain largely unknown, but recent studies indicate that the cellular and plasma levels of adiponectin could be regulated at both transcriptional and post-transcriptional levels. At the post-translational level, TZDs and resveratrol promote adiponectin levels and multimerization via up-regulation of disulfide-bond-A oxidoreductase-like protein (DsbA-L). Adiponectin levels are also stimulated by FOXO1 and AMP-activated protein kinase (AMPK), and are suppressed by PKA or silencing mediator of retinoid and thyroid hormone receptors (SMRT). Since multimerization is important not only for adiponectin function but also for stability, increasing adiponectin multimerization has become a promising drug target for the treatment of metabolic diseases and other related disorders.
Topics: Adiponectin; Animals; Down-Regulation; Humans; PPAR gamma; Protein Multimerization; Small Molecule Libraries; Up-Regulation
PubMed: 22342903
DOI: 10.1016/j.biochi.2012.01.008 -
Nature Oct 2017Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader...
Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine. Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners, including transcriptional co-repressors (for example, the NCoR/SMRT complex), transcriptional activators, RNA, chromatin remodellers, microRNA-processing proteins and splicing factors. Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons. At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain and the NCoR/SMRT interaction domain. Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.
Topics: 3T3 Cells; Animals; Brain; DNA; Genetic Complementation Test; Genetic Therapy; HeLa Cells; Humans; Male; Methyl-CpG-Binding Protein 2; Mice; Mutation, Missense; Phenotype; Protein Domains; Protein Stability; Rett Syndrome; Sequence Deletion; Transduction, Genetic
PubMed: 29019980
DOI: 10.1038/nature24058