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1.
Nat Commun ; 12(1): 1026, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589589

RESUMO

Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with virus and genetic tracings, we molecularly identify three main types of PNs (Ia, Ib and II) and find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles. Altogether, these features contribute to finely regulate proprioception during complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later in life along with increased motor activity. We also show Ia-PNs plasticity following exercise training, suggesting Ia-PNs are important players in adaptive proprioceptive function in adult mice.


Assuntos
Retroalimentação Sensorial/fisiologia , Gânglios Espinais/metabolismo , Neurônios Motores/metabolismo , Propriocepção/fisiologia , Células Receptoras Sensoriais/metabolismo , Animais , Calbindina 1/genética , Calbindina 1/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Gânglios Espinais/citologia , Expressão Gênica , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/classificação , Neurônios Motores/citologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Condicionamento Físico Animal , Células Receptoras Sensoriais/classificação , Células Receptoras Sensoriais/citologia , Análise de Célula Única , Medula Espinal/citologia , Medula Espinal/metabolismo
2.
Nat Commun ; 12(1): 734, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531470

RESUMO

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.


Assuntos
Proteínas Nucleares/metabolismo , Proteínas Oncogênicas/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/metabolismo , Regulador Transcricional ERG/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Imuno-Histoquímica , Imunoprecipitação , Masculino , Camundongos , Camundongos Nus , Mutação/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Neoplasias da Próstata/genética , Ligação Proteica , Proteômica , Receptores Androgênicos/metabolismo , Proteínas Repressoras/genética , Transdução de Sinais/fisiologia , Regulador Transcricional ERG/genética , Complexos Ubiquitina-Proteína Ligase/genética
3.
Biochem Biophys Res Commun ; 545: 164-170, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33571907

RESUMO

Mammalian Transducin-like enhancer of split (TLE) confer global repression of numerous target genes in conjunction with a myriad of DNA-binding repressors. These factors have a major role in the regulation of multiple signal transduction pathways. Evidence have been obtained regarding the possible role of some of these proteins in cancer. TLE3 was suggested as a marker for increased chemosensitivity from pathological studies. Here we demonstrate, using the TCGA data base, differences in expression of this gene compared to TLE1 in several cancers. In-vitro transduction of a retrovirus encoding TLE3 to A549 lung cancer cells increased paclitaxel effectivity while TLE1 introduction to these cells decreased it. While TLE1 and TLE3 share ∼80% amino acid identity, we show that mutating or reconstituting an amino-terminal phosphorylation site, which is present only in TLE1 but absent from TLE3, and is evolutionary conserved, converts the activity of TLE1 to that of TLE3 like and vice versa. We repeated these results in an adipocytes differentiation system. Our results reveal how a single phosphorylation site can confer distinct qualitative or quantitative activities on highly homologous transcriptional regulators.


Assuntos
Proteínas Correpressoras/química , Proteínas Correpressoras/metabolismo , Células A549 , Adipócitos/citologia , Adipócitos/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sítios de Ligação/genética , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Linhagem Celular , Proteínas Correpressoras/genética , Sequência Conservada , Regulação da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Mutagênese Sítio-Dirigida , Fosforilação , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Taxoides/farmacologia
4.
Mol Cell ; 81(5): 953-968.e9, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33503407

RESUMO

While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates in vivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases.


Assuntos
Quimiocina CCL2/genética , Proteínas Correpressoras/genética , Elementos Facilitadores Genéticos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Correpressor 2 de Receptor Nuclear/genética , Obesidade/genética , Elementos Silenciadores Transcricionais , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Sistemas CRISPR-Cas , Quimiocina CCL2/imunologia , Proteínas Correpressoras/imunologia , Edição de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Histona Acetiltransferases/genética , Histona Acetiltransferases/imunologia , Histonas/genética , Histonas/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/imunologia , Camundongos , Camundongos Obesos , Correpressor 2 de Receptor Nuclear/imunologia , Obesidade/imunologia , Obesidade/patologia , Células RAW 264.7 , RNA não Traduzido/genética , RNA não Traduzido/imunologia , Transdução de Sinais
5.
J Clin Pathol ; 74(3): 137-140, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33441390

RESUMO

TLE 1 is the human homologue belonging to a family of four genes and is located on chromosome 9q21. It consists of 19 exons. Although it does not bind directly to DNA, it acts as a repressor of several signalling pathways via transcription factors. TLE1 protein has several physiological roles in embryogenesis, haematopoiesis, general differentiation, and both neuronal and eye development. Much attention was focused on its expression in the tumour cell nuclei of synovial sarcoma (SS). However, several other soft tissue tumours that do and do not share morphological similarity with SS also display nuclear immunoreactivity for TLE1; hence, caution in interpretation is advocated.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Correpressoras/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Neoplasias de Tecidos Moles/metabolismo , Núcleo Celular/patologia , Proteínas Correpressoras/metabolismo , Humanos , Imuno-Histoquímica , Oncogenes/genética , Neoplasias de Tecidos Moles/patologia
6.
Plant Mol Biol ; 105(4-5): 463-482, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33474657

RESUMO

KEY MESSAGE: SCL3 inhibits transcriptional activity of IDD-DELLA complex by acting as a co-repressor and repression activity is enhanced in the presence of GAF1 in a TOPLESS-independent manner. GRAS [GIBBERELLIN-INSENSITIVE (GAI), REPRESSOR OF ga1-3 (RGA) and SCARECROW (SCR)] proteins are a family of plant-specific transcriptional regulators that play diverse roles in development and signaling. GRAS family DELLA proteins act as growth repressors by inhibiting gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also act as co-activators of transcription factor GAI-ASSOCIATED FACTOR1 (GAF1)/INDETERMINATE DOMAIN2 (IDD2), the GAF1-DELLA complex activating transcription of GAF1 target genes. GAF1 also interacts with TOPLESS (TPL), a transcriptional co-repressor, in the absence of DELLA, the GAF1-TPL complex repressing transcription of the target genes. SCARECROW-LIKE3 (SCL3), another member of the GRAS family, is thought to inhibit transcriptional activity of the IDD-DELLA complex through competitive interaction with IDD. Here, we also revealed that SCL3 inhibits transcriptional activation by the GAF1-DELLA complex via repression activity rather than via competitive inhibition of the GAF1-DELLA interaction. Moreover, the repression activity of SCL3 was enhanced by GAF1 in a TPL-independent manner. While the GRAS domain of DELLA has transcriptional activation activity, that of SCL3 has repression activity. SCL3 also inhibited transcriptional activity of GAF1-RGA fusion proteins. Results from the co-immunoprecipitation assays and the yeast three-hybrid assay suggested the possibility that SCL3 forms a ternary complex with GAF1 and DELLA. These findings provide important information on DELLA-regulated GA signaling and new insight into the transcriptional repression mechanism.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas Correpressoras/genética , Regulação da Expressão Gênica de Plantas , Giberelinas/metabolismo , Ribonuclease P/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas Correpressoras/metabolismo , Immunoblotting , Ligação Proteica , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonuclease P/metabolismo , Transdução de Sinais/genética , Técnicas do Sistema de Duplo-Híbrido
7.
Am J Hum Genet ; 107(4): 622-635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946763

RESUMO

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.


Assuntos
Carcinoma Epitelial do Ovário/genética , Proteínas Correpressoras/genética , Cistadenocarcinoma Seroso/genética , Elementos Facilitadores Genéticos , Histonas/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Ovarianas/genética , Alelos , Sítios de Ligação , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/patologia , Mapeamento Cromossômico , Proteínas Correpressoras/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Feminino , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Padrões de Herança , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Penetrância , Polimorfismo de Nucleotídeo Único , Risco
8.
Mol Cell ; 78(5): 903-914.e4, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32396821

RESUMO

LSD1 (lysine specific demethylase; also known as KDM1A), the first histone demethylase discovered, regulates cell-fate determination and is overexpressed in multiple cancers. LSD1 demethylates histone H3 Lys4, an epigenetic mark for active genes, but requires the CoREST repressor to act on nucleosome substrates. To understand how an accessory subunit (CoREST) enables a chromatin enzyme (LSD1) to function on a nucleosome and not just histones, we have determined the crystal structure of the LSD1/CoREST complex bound to a 191-bp nucleosome. We find that the LSD1 catalytic domain binds extranucleosomal DNA and is unexpectedly positioned 100 Å away from the nucleosome core. CoREST makes critical contacts with both histone and DNA components of the nucleosome, explaining its essential function in demethylating nucleosome substrates. Our studies also show that the LSD1(K661A) frequently used as a catalytically inactive mutant in vivo (based on in vitro peptide studies) actually retains substantial H3K4 demethylase activity on nucleosome substrates.


Assuntos
Histona Desmetilases/metabolismo , Histona Desmetilases/ultraestrutura , Sequência de Aminoácidos , Domínio Catalítico , Cromatina/metabolismo , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Cristalografia por Raios X/métodos , DNA/genética , DNA/metabolismo , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Metilação , Modelos Moleculares , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nucleossomos/química , Nucleossomos/genética , Nucleossomos/metabolismo , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica
9.
Oncogene ; 39(21): 4212-4226, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32251364

RESUMO

Impaired neuronal differentiation is a feature of neuroblastoma tumorigenesis, and the differentiation grade of neuroblastoma tumors is associated with patient prognosis. Detailed understanding of the molecular mechanisms underlying neuroblastoma differentiation will facilitate the development of effective treatment strategies. Recent studies have shown that myelin transcription factor 1 (MYT1) promotes vertebrate neurogenesis by regulating gene expression. We performed quantitative analysis of neuroblastoma samples, which revealed that MYT1 was differentially expressed among neuroblastoma patients with different pathological diagnoses. Analysis of clinical data showed that MYT1 overexpression was associated with a significantly shorter 3-year overall survival rate and poor differentiation in neuroblastoma specimens. MYT1 knockdown inhibited proliferation and promoted the expression of multiple differentiation-associated proteins. Integrated omics data indicated that many genes involved in neuro-differentiation were regulated by MYT1. Interestingly, many of these genes are targets of the REST complex; therefore, we further identified the physical interaction of MYT1 with LSD1/CoREST. Depletion of LSD1 or inhibition of LSD1 by ORY-1001 decreased MYT1 expression, providing an alternative approach to target MYT1. Taken together, our results indicate that MYT1 significantly attenuates cell differentiation by interacting with the LSD1/CoREST complex. MYT1 is, therefore, a promising therapeutic target for enhancing the neurite-inducing effect of retinoic acid and for inhibiting the growth of neuroblastoma.


Assuntos
Diferenciação Celular , Proteínas Correpressoras/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histona Desmetilases/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroblastoma/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas Correpressoras/genética , Proteínas de Ligação a DNA/genética , Feminino , Histona Desmetilases/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Complexos Multiproteicos/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Neuroblastoma/genética , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Fatores de Transcrição/genética
10.
J Pharmacol Sci ; 143(2): 74-82, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32192854

RESUMO

BACKGROUND: Circular RNAs (circRNAs) play an important role in the tumorigenesis of glioma. Our study indicated that low hsa_circ_0008225 expression was associated with poor overall survival in patients with glioma. However, the relevant mechanism of hsa_circ_0008225 in glioma tumorigenesis remains unclear. METHODS: Two datasets (GSE86202 and GSE92322) were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed circRNAs (DEcircRNAs) between glioma tissues and matched normal tissues were screened using R language. RESULTS: A total of 79 overlapping DEcircRNAs were identified by comparison of glioma and matched normal tissues. In addition, low hsa_circ_0008225 expression was associated with poor overall survival in patients with glioma. Overexpression of hsa_circ_0008225 markedly inhibited the proliferation, migration and invasion of SHG44 cells via inducing apoptosis. Mechanically, overexpression of hsa_circ_0008225 increased the expression of miR-890 targeted gene ZMYND11 via acting as a competitive 'sponge' of miR-890. CONCLUSION: Our results suggested that hsa_circ_0008225 functions as a tumor inhibitor in glioma by sponging miR-890 and then promoting the function of ZMYND11. Therefore, hsa_circ_0008225 could be a potential prognostic biomarker for the treatment of glioma.


Assuntos
Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Glioma/genética , Glioma/patologia , MicroRNAs , RNA Circular/fisiologia , Apoptose/genética , Movimento Celular/genética , Expressão Gênica , Glioma/mortalidade , Humanos , Invasividade Neoplásica/genética , RNA Circular/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
11.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(1): 7-15, 2020 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-32131934

RESUMO

Objective To unravel the role of hematopoietic pre-B-cell leukemia transcription factor interacting protein(HPIP)in the proliferation,cell cycle,and apoptosis of pancreatic ductal adenocarcinoma(PDAC)cells. Methods The HPIP expression in PDAC tissue was determined by immunohistochemical staining.Knockdown of HPIP was accomplished in MIA PaCa-2 and BxPC-3 cell lines by transient transfection of HPIP siRNA and validated by Western blotting.Cell proliferation was assessed using the cell counting kit-8 assay and colony formation assay.Cell cycle and apoptosis were detected by flow cytometry.Western blotting was performed to detect the expression levels of cyclin D1,caspase 7,and cleaved caspase 7. Results HPIP was overexpressed in PDAC tissue compared with matched adjacent pancreatic tissue(Z=-2.060,P=0.039).Knockdown of HPIP inhibited the proliferation of MIA PaCa-2 and BxPC-3 cells(all P<0.05).Knockdown of HPIP significantly reduced the positive colonies formed by MIA PaCa-2 and BxPC-3 cells(t=4.706,P=0.009;t=9.514,P=0.000).Knockdown of HPIP decreased the proportion of S phase cells(t=7.642,P=0.001;t=2.714,P=0.051)and increased the proportion of G0/G1 phase cells(t=3.244,P=0.031;t=6.095,P=0.003)in MIA PaCa-2 and BxPC-3 cells.Meanwhile,knockdown of HPIP increased the proportions of late-phase MIA PaCa-2 and BxPC-3 cells(t=24.58,P=0.000;t=36.45,P=0.000)and the overall apoptosis rate(t=29.43,P=0.000;t=43.52,P=0.000).In MIA PaCa-2 and BxPC-3 cells,knockdown of HPIP decreased the expression level of cyclin D1(t=6.705,P=0.002;t=6.238,P=0.003)and increased the expression level of cleaved caspase 7(t=3.991,P=0.016;t=6.536,P=0.002). Conclusions HPIP is overexpressed in PDAC tissue.Knockdown of HPIP inhibits the proliferation and G0/G1 to S transition of PDAC cells.Meanwhile,knockdown of HPIP promotes the apoptosis of PDAC cells.Thus,HPIP may act as an oncogene in PDAC.


Assuntos
Adenocarcinoma/patologia , Apoptose , Ciclo Celular , Proliferação de Células , Proteínas Correpressoras/genética , Neoplasias Pancreáticas/patologia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos
12.
Arterioscler Thromb Vasc Biol ; 40(5): 1256-1274, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32160773

RESUMO

OBJECTIVE: In view of our previous observations on differential expression of LMCD1 (LIM and cysteine-rich domains 1) in human versus rodents, we asked the question whether LMCD1 plays a species-specific role in the development of vascular lesions. Approach and Results: A combination of genetic, molecular, cellular, and disease models were used to test species-specific role of LMCD1 in the pathogenesis of vascular lesions. Here, we report species-specific regulation of LMCD1 expression in mediating vascular smooth muscle cell proliferation and migration during vascular wall remodeling in humans versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells but not mouse aortic smooth muscle cells via activation of Par1 (protease-activated receptor 1)-Gαq/11 (Gα protein q/11)-PLCß3 (phospholipase Cß3)-NFATc1 (nuclear factor of activated T cells 1) signaling. Furthermore, although LMCD1 mediates thrombin-induced proliferation and migration of both human aortic smooth muscle cells and mouse aortic smooth muscle cells via influencing E2F1 (E2F transcription factor 1)-mediated CDC6 (cell division cycle 6) expression and NFATc1-mediated IL (interleukin)-33 expression, respectively, in humans, it acts as an activator, and in mice, it acts as a repressor of these transcriptional factors. Interestingly, LMCD1 repressor activity was nullified by N-myristoyltransferase 2-mediated myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to nonstenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to noninjured arteries. CONCLUSIONS: Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in humans and mice, respectively, in the induction of CDC6 and IL-33 expression during development of vascular lesions. Based on these findings, LMCD could be a potential target for drug development against restenosis and atherosclerosis in humans.


Assuntos
Proteínas Correpressoras/metabolismo , Fator de Transcrição E2F1/metabolismo , Interleucina-33/metabolismo , Proteínas com Domínio LIM/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição NFATC/metabolismo , Remodelação Vascular , Lesões do Sistema Vascular/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Proteínas Correpressoras/genética , Modelos Animais de Doenças , Fator de Transcrição E2F1/genética , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-33/genética , Proteínas com Domínio LIM/genética , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Ácido Mirístico/metabolismo , Fatores de Transcrição NFATC/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Especificidade da Espécie , Trombina/farmacologia , Remodelação Vascular/efeitos dos fármacos , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia
13.
J Clin Pathol ; 73(6): 314-317, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32161069

RESUMO

BCL-6 transcriptional corepressor (BCOR) gene is located at Xp11.4 and encodes a protein which is involved in transcriptional repression in association with BCL-6 and epigenetic silencing through polycomb repressive complex 1 (PRC1). BCOR mutations are being identified in an increasing number of tumours which are diverse in their anatomical location and clinical setting. Interestingly, these tumours share similar and overlapping histological features, namely small round blue cell morphology and a myxoid background with delicate capillary channels. Clear cell sarcoma of the kidney, primitive myxoid mesenchymal tumour of infancy and central nervous system high-grade neuroepithelial tumour with BCOR alteration all share similar internal tandem duplications in the polycomb-group really interesting new gene (RING) finger homolog ubiquitin-likefold discriminator domain of BCOR Translocations resulting in BCOR fusion with CCNB3, MAML3 and ZC3H7B have been identified in undifferentiated round cell sarcoma. Subsets of high-grade endometrial stromal sarcoma and ossifying fibromyxoid tumour which have a more aggressive clinical course have been shown to harbour ZC3H7B-BCOR fusions. BCOR immunohistochemistry is an established marker with diagnostic utility.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Translocação Genética , Biomarcadores Tumorais/metabolismo , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Epigênese Genética , Duplicação Gênica , Fusão Gênica , Inativação Gênica , Humanos , Imuno-Histoquímica , Neoplasias/diagnóstico , Neoplasias/patologia , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Repressoras/metabolismo
14.
Sci Adv ; 6(11): eaay4697, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32201722

RESUMO

Previously, we reported that chromodomain Y-like (CDYL) acts as a crotonyl-coenzyme A hydratase and negatively regulates histone crotonylation (Kcr). However, the global CDYL-regulated crotonylome remains unclear. Here, we report a large-scale proteomics analysis for protein Kcr. We identify 14,311 Kcr sites across 3734 proteins in HeLa cells, providing by far the largest crotonylome dataset. We show that depletion of CDYL alters crotonylome landscape affecting diverse cellular pathways. Specifically, CDYL negatively regulated Kcr of RPA1, and mutation of the Kcr sites of RPA1 impaired its interaction with single-stranded DNA and/or with components of resection machinery, supporting a key role of RPA1 Kcr in homologous recombination DNA repair. Together, our study indicates that protein crotonylation has important implication in various pathophysiological processes.


Assuntos
Proteínas Correpressoras/metabolismo , Hidroliases/metabolismo , Processamento de Proteína Pós-Traducional , Reparo de DNA por Recombinação , Proteína de Replicação A/metabolismo , Sobrevivência Celular/genética , Proteínas Correpressoras/genética , Dano ao DNA , DNA de Cadeia Simples/genética , Técnicas de Silenciamento de Genes , Células HeLa , Histonas/metabolismo , Humanos , Hidroliases/genética , Proteoma
15.
Nat Commun ; 11(1): 733, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024817

RESUMO

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.


Assuntos
Mutação , Neoplasias/genética , Telômero/genética , Estudos de Casos e Controles , Proteínas Correpressoras/genética , Genoma Humano , Humanos , Chaperonas Moleculares/genética , RNA Longo não Codificante , Sequências Repetitivas de Ácido Nucleico , Telomerase/genética , Sequenciamento Completo do Genoma , Proteína Nuclear Ligada ao X/genética
17.
PLoS One ; 15(1): e0227355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990937

RESUMO

Incomplete hippocampal inversion (IHI), also called hippocampal malrotation, is an atypical presentation of the hippocampus present in about 20% of healthy individuals. Here we conducted the first genome-wide association study (GWAS) in IHI to elucidate the genetic underpinnings that may contribute to the incomplete inversion during brain development. A total of 1381 subjects contributed to the discovery cohort obtained from the IMAGEN database. The incidence rate of IHI was 26.1%. Loci with P<1e-5 were followed up in a validation cohort comprising 161 subjects from the PING study. Summary statistics from the discovery cohort were used to compute IHI heritability as well as genetic correlations with other traits. A locus on 18q11.2 (rs9952569; OR = 1.999; Z = 5.502; P = 3.755e-8) showed a significant association with the presence of IHI. A functional annotation of the locus implicated genes AQP4 and KCTD1. However, neither this locus nor the other 16 suggestive loci reached a significant p-value in the validation cohort. The h2 estimate was 0.54 (sd: 0.30) and was significant (Z = 1.8; P = 0.036). The top three genetic correlations of IHI were with traits representing either intelligence or education attainment and reached nominal P< = 0.013.


Assuntos
Encefalopatias/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipocampo/fisiopatologia , Adolescente , Aquaporina 4/genética , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Proteínas Correpressoras/genética , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Lobo Temporal/fisiopatologia
18.
J Biol Chem ; 295(7): 1879-1888, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31932307

RESUMO

The homeodomain protein NK2 homeobox 2 (NKX2-2) is a transcription factor that plays a critical role in the control of cell fate specification and differentiation in many tissues. In the developing central nervous system, this developmentally important transcription factor functions as a transcriptional repressor that governs oligodendrocyte (OL) differentiation and myelin gene expression, but the roles of various NKX2-2 structural domains in this process are unclear. In this study, using in situ hybridization, immunofluorescence, and coimmunoprecipitation, we determined the structural domains that mediate the repressive functions of murine NKX2-2 and identified the transcriptional corepressors that interact with it in OL cells. Through in ovo electroporation in embryonic chicken spinal cords, we demonstrate that the N-terminal Tinman domain and C-terminal domain synergistically promote OL differentiation by recruiting distinct transcriptional corepressors, including enhancer of split Groucho 3 (GRG3), histone deacetylase 1 (HDAC1), and DNA methyltransferase 3 α (DNMT3A). We also observed that the NK2-specific domain suppresses the function of the C-terminal domain in OL differentiation. These findings delineate the distinct NKX2-2 domains and their roles in OL differentiation and suggest that NKX2-2 regulates differentiation by repressing gene expression via multiple cofactors and molecular mechanisms.


Assuntos
Diferenciação Celular/genética , Proteínas de Homeodomínio/genética , Neurogênese/genética , Proteínas de Peixe-Zebra/genética , Animais , Embrião de Galinha , Proteínas Correpressoras/genética , DNA (Citosina-5-)-Metiltransferases/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Histona Desacetilase 1/genética , Proteínas de Homeodomínio/química , Camundongos , Oligodendroglia/metabolismo , Regiões Promotoras Genéticas/genética , Domínios Proteicos/genética , Fatores de Transcrição/genética
19.
Biochem Biophys Res Commun ; 523(2): 354-360, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31866012

RESUMO

The epithelial to mesenchymal transition (EMT) is a cell intrinsic program controlling cellular morphological and phenotypic remodeling in a wide range of biological processes. Despite the accumulating evidence, the transcriptional networks regulating EMT still remain to be elucidated. In this study, we demonstrate that C-terminal binding protein 2 (CtBP2), a critical transcriptional co-repressor harboring pyridine nucleotide sensing capability, orchestrates the EMT program at least in part through a novel transcriptional interaction with an octamer transcription factor, OCT1 (POU2F1, POU class 2 homeobox 1). We identified novel interactions of CtBP2 with several octamer transcription factors, and CtBP2 exhibits a direct interaction with OCT1 in particular. OCT1 accelerates the EMT program as reported, which is diminished by the mutation of the CtBP-binding motif in OCT1, suggesting OCT1 represses epithelial gene expression through recruiting the co-repressor CtBP2. In accordance with these findings, a canonical EMT activator transforming growth factor-ß (TGF-ß) promotes the formation of the CtBP2/OCT1 complex. Our observations illustrate the role of CtBP2 to orchestrate the EMT program through the interaction with OCT1 and highlight the potential of therapeutic exploitation of this new transcriptional system for a wide range of diseases.


Assuntos
Oxirredutases do Álcool/metabolismo , Proteínas Correpressoras/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Fator 1 de Transcrição de Octâmero/metabolismo , Oxirredutases do Álcool/química , Oxirredutases do Álcool/genética , Sequência de Aminoácidos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteínas Correpressoras/química , Proteínas Correpressoras/genética , Sequência Conservada , Transição Epitelial-Mesenquimal/genética , Feminino , Redes Reguladoras de Genes , Humanos , Células MCF-7 , Camundongos , Mutação , Fator 1 de Transcrição de Octâmero/química , Fator 1 de Transcrição de Octâmero/genética , Domínios e Motivos de Interação entre Proteínas , Ratos , Fator de Crescimento Transformador beta/metabolismo
20.
Mol Cell ; 77(2): 338-351.e6, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31732456

RESUMO

Ants acquire distinct morphological and behavioral phenotypes arising from a common genome, underscoring the importance of epigenetic regulation. In Camponotus floridanus, "Major" workers defend the colony, but can be epigenetically reprogrammed to forage for food analogously to "Minor" workers. Here, we utilize reprogramming to investigate natural behavioral specification. Reprogramming of Majors upregulates Minor-biased genes and downregulates Major-biased genes, engaging molecular pathways fundamental to foraging behavior. We discover the neuronal corepressor for element-1-silencing transcription factor (CoREST) is upregulated upon reprogramming and required for the epigenetic switch to foraging. Genome-wide profiling during reprogramming reveals CoREST represses expression of enzymes that degrade juvenile hormone (JH), a hormone elevated upon reprogramming. High CoREST, low JH-degrader expression, and high JH levels are mirrored in natural Minors, revealing parallel mechanisms of natural and reprogrammed foraging. These results unveil chromatin regulation via CoREST as central to programming of ant social behavior, with potential far-reaching implications for behavioral epigenetics.


Assuntos
Formigas/genética , Formigas/fisiologia , Comportamento Animal/fisiologia , Proteínas Correpressoras/genética , Epigênese Genética/genética , Proteínas de Insetos/genética , Animais , Cromatina/genética , Genoma/genética , Hormônios Juvenis/genética , Neurônios/fisiologia , Comportamento Social
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