RÉSUMÉ
The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity.
Sujet(s)
Système de conduction du coeur , Protéines à homéodomaine , Myocytes cardiaques , Protéines à domaine boîte-T , Animaux , Protéines à domaine boîte-T/génétique , Protéines à domaine boîte-T/métabolisme , Souris , Myocytes cardiaques/métabolisme , Système de conduction du coeur/métabolisme , Protéines à homéodomaine/génétique , Protéines à homéodomaine/métabolisme , Réseaux de régulation génique , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Régulation de l'expression des gènes , Animaux nouveau-nés , Analyse sur cellule unique , Transcriptome , Fibres de Purkinje/métabolisme , Fibres de Purkinje/physiologie , Noeud atrioventriculaire/métabolisme , Noeud sinuatrial/métabolisme , Faisceau de His/métabolismeRÉSUMÉ
Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic condition affecting the autonomic nervous system and respiratory center due to mutations in the PHOX2B gene, and it is associated with alveolar hypoventilation during sleep and sudden death. It requires early invasive mechanical ventilation (IMV). OBJECTIVE: To report a neonatal case successfully treated with non-invasive ventilatory support (NVS), avoiding tracheostomy. CLINICAL CASE: Full-term newborn, whose mother uses nocturnal NVS due to CCHS. During the transition period, she presented desaturations associated with hypercapnia and respiratory acidosis, without pulmonary involvement. She developed severe hypoventilation during sleep, with no respiratory effort, peripheral oxygen saturation (SpO2) < 80%, plus respiratory acidosis. While awake, she had good respiratory effort and normal SpO2 without assistance. Noninvasive continuous positive airway pressure and oxygen therapy worsened her condition while sleeping. Complete NVS with nasal interface and bi-level airway positive pressure, inspiratory/expiratory pressure 14-16/4 cm H2O, normalized SpO2 during sleep, and arterial blood gases while awake. Sequencing of the PHOX2B gene confirmed the presence of a heterozygous pathogenic variant with the 20/26 genotype. At 2 months of age, she was discharged maintaining NVS with nasal interface and 0 PEEP, achieving adequate neurodevelopment. CONCLUSION: We highlight the importance of genetic diagnosis of CCHS in neonates with clinical presentation of early alveolar hypoventilation, especially if there is a family history. We are not aware of other reports of neonatal onset in which NVS prevents IMV, in this potentially lethal pathology.
Sujet(s)
Protéines à homéodomaine , Hypoventilation , Apnée centrale du sommeil , Facteurs de transcription , Humains , Apnée centrale du sommeil/diagnostic , Apnée centrale du sommeil/thérapie , Apnée centrale du sommeil/génétique , Nouveau-né , Hypoventilation/congénital , Hypoventilation/thérapie , Hypoventilation/diagnostic , Hypoventilation/génétique , Femelle , Protéines à homéodomaine/génétique , Facteurs de transcription/génétique , Ventilation non effractive , Ventilation en pression positive continue , Acidose respiratoire/diagnostic , Acidose respiratoire/thérapie , Acidose respiratoire/étiologie , Mutation , OxygénothérapieRÉSUMÉ
The chromosomes in multicellular eukaryotes are organized into a series of topologically independent loops called TADs. In flies, TADs are formed by physical interactions between neighboring boundaries. Fly boundaries exhibit distinct partner preferences, and pairing interactions between boundaries are typically orientation-dependent. Pairing can be head-to-tail or head-to-head. The former generates a stem-loop TAD, while the latter gives a circle-loop TAD. The TAD that encompasses the Drosophila even skipped (eve) gene is formed by the head-to-tail pairing of the nhomie and homie boundaries. To explore the relationship between loop topology and the physical and regulatory landscape, we flanked the nhomie boundary region with two attP sites. The attP sites were then used to generate four boundary replacements: λ DNA, nhomie forward (WT orientation), nhomie reverse (opposite of WT orientation), and homie forward (same orientation as WT homie). The nhomie forward replacement restores the WT physical and regulatory landscape: in MicroC experiments, the eve TAD is a 'volcano' triangle topped by a plume, and the eve gene and its regulatory elements are sequestered from interactions with neighbors. The λ DNA replacement lacks boundary function: the endpoint of the 'new' eve TAD on the nhomie side is ill-defined, and eve stripe enhancers activate a nearby gene, eIF3j. While nhomie reverse and homie forward restore the eve TAD, the topology is a circle-loop, and this changes the local physical and regulatory landscape. In MicroC experiments, the eve TAD interacts with its neighbors, and the plume at the top of the eve triangle peak is converted to a pair of 'clouds' of contacts with the next-door TADs. Consistent with the loss of isolation afforded by the stem-loop topology, the eve enhancers weakly activate genes in the neighboring TADs. Conversely, eve function is partially disrupted.
Sujet(s)
Protéines de Drosophila , Animaux , Protéines de Drosophila/génétique , Protéines de Drosophila/métabolisme , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Protéines à homéodomaine/métabolisme , Protéines à homéodomaine/génétique , Drosophila melanogaster/génétique , Drosophila/génétiqueRÉSUMÉ
The LBX1 gene is located near a single nucleotide polymorphism that is highly associated with susceptibility to adolescent idiopathic scoliosis and is considered one of the strongest candidate genes involved in the pathogenesis of this condition. We have previously found that loss of LBX1 from skeletal muscle results not only in spinal deformity but also in lean body mass, suggesting a potential role for LBX1 in energy metabolism. The purpose of the present study was to test this hypothesis by analyzing the phenotype of mice lacking LBX1 in skeletal muscle with a focus on energy metabolism. We found that loss of LBX1 rendered mice more resistant to high-fat diet-induced obesity, despite comparable food intake between mutant and control mice. Notably, the mutant mice exhibited improved glucose tolerance, increased maximal aerobic capacity, and higher core body temperature compared to control mice. In addition, we found that overexpression of LBX1 decreased glucose uptake in cultured cells. Taken together, our data show that LBX1 functions as a negative regulator of energy metabolism and that loss of LBX1 from skeletal muscle increases systemic energy expenditure resulting in lean body mass. The present study thus suggests a potential association between LBX1 dysfunction and lean body mass in patients with adolescent idiopathic scoliosis.
Sujet(s)
Métabolisme énergétique , Muscles squelettiques , Animaux , Souris , Muscles squelettiques/métabolisme , Obésité/métabolisme , Obésité/génétique , Alimentation riche en graisse/effets indésirables , Glucose/métabolisme , Mâle , Humains , Souris knockout , Protéines à homéodomaine/génétique , Protéines à homéodomaine/métabolisme , Scoliose/génétique , Scoliose/métabolisme , Souris de lignée C57BLRÉSUMÉ
OBJECTIVES: To comprehensively investigate the potential association between prostate cancer (PCa) and the G84E mutation within the Homeobox Protein B13 (HOXB13) gene among individuals of Turkish descent, our study aims to undertake a prospective examination. METHODS: We evaluated 300 patients (150 diagnosed with prostate cancer, 150 controls) who presented in our clinic. Data collected were prospectively examined. DNA isolation was performed using an isolation kit. The HOXB13-G84E mutation (rs138213197) was analyzed in the obtained samples. Data encoding and statistical analysis were performed. RESULTS: The pathological allele for the G84E mutation was T. According to the findings, no mutations were detected in the control group, while the G84E mutation was detected in 17 patients in the patient group, all of whom had the TC genotype. The analysis showed that having the CC genotype reduced the risk of prostate cancer by 0.47 times (OR=0.47, CI=0.415-0.532). Our results did not support a trend toward family history or earlier-onset disease in comparisons between carriers and non-carriers of HOXB13 G84E mutation. Individuals with a positive family history exhibited a higher frequency of the G84E mutation. CONCLUSIONS: We concluded that HOXB13 gene mutation is indeed linked to PCa in Turkish men. However, we did not find a relationship between the HOXB13 gene G84E mutation carrier status and either early-onset PCa or familial PCa in Turkish men.
Sujet(s)
Protéines à homéodomaine , Mutation , Tumeurs de la prostate , Humains , Mâle , Protéines à homéodomaine/génétique , Tumeurs de la prostate/génétique , Sujet âgé , Adulte d'âge moyen , Turquie , Études prospectives , Génotype , Études cas-témoinsRÉSUMÉ
BACKGROUND: The Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented. CASE PRESENTATION: The proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4-10 of the CUX1 gene. CONCLUSIONS: Our review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development.
Sujet(s)
Protéines à homéodomaine , Protéines de répression , Humains , Mâle , Protéines à homéodomaine/génétique , Adolescent , Protéines de répression/génétique , Facteurs de transcription/génétique , Développement sexuel/génétiqueRÉSUMÉ
BACKGROUND: IDH1 mutations are common in many cancers, however, their role in promoting the Warburg effect remains elusive. This study elucidates the putative involvement of mutant-IDH1 in regulating hypoxia-inducible factor (HIF1-α) and Sine-Oculis Homeobox-1 (SIX-1) expression. METHODOLOGY: Genetic screening was performed using the ARMS-PCR in acute myeloid leukemia (AML), brain, and breast cancer (BC) cohorts, while transcript expression was determined using qPCR. Further, a meta-analysis of risk factors associated with the R132 mutation was performed. RESULTS: Approximately 32% of AML and â¼60% of glioma cases were mutants, while no mutation was found in the BC cohort. 'AA' and TT' were associated with higher disease risk (OR = 12.18 & 4.68) in AML and had significantly upregulated IDH1 expression. Moreover, downregulated HIF1-α and upregulated SIX-1 expression was also observed in these patients, suggesting that mutant-IDH1 may alter glucose metabolism. Perturbed IDH1 and HIF-α levels exhibited poor prognosis in univariate and multivariate analysis, while age and gender were found to be contributory factors as well. Based on the ROC model, these had a good potential to be used as prognostic markers. A significant variation in frequencies of R132 mutations in AML among different populations was observed. Cytogenesis (R2 = 12.2%), NMP1 mutation status (R2 = 18.5%), and ethnic contributions (R2 = 73.21%) were critical moderators underlying these mutations. Women had a higher risk of R132 mutation (HR = 1.3, P < 0.04). The pooled prevalence was calculated to be 0.29 (95% CI 0.26-0.33, P < 0.01), indicating that IDH1 mutations are a significant prognostic factor in AML. CONCLUSION: IDH1 and HIF1-α profiles are linked to poor survival and prognosis, while high SIX-1 expression in IDH1 mutants suggests a role in leukemic transformation and therapy response in AML.
IDH1 mutations are common in many types of cancer, but scientists have not fully understood how they contribute to the Warburg effect - a process that alters glucose metabolism in cells. In this study, we evaluate the association between mutant-IDH1 and HIF1 as well as SIX-1 gene expression. We analyzed genetic data from patients with brain cancer, breast cancer, and acute myeloid leukemia (AML), and found that roughly 32% of AML cases and 60% of glioma cases had IDH1 mutations, while no mutations were found in breast cancer. Patients with mutant genotypes had a higher risk of disease and showed upregulated IDH1 expression. They also had downregulated HIF1 and upregulated SIX-1 expression, suggesting that mutant-IDH1 can change glucose metabolism in cancer cells. Patients with abnormal IDH1 and HIF1 levels were more likely to have a poor prognosis. Further, we identified several risk factors that can influence IDH1 mutations, including cytogenesis, NMP1 mutation status, and ethnicity. The researchers calculated that IDH1 mutations are a significant factor in predicting outcomes for AML.
Sujet(s)
Protéines à homéodomaine , Sous-unité alpha du facteur-1 induit par l'hypoxie , Isocitrate dehydrogenases , Leucémie aigüe myéloïde , Mutation , Humains , Isocitrate dehydrogenases/génétique , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/métabolisme , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Femelle , Pronostic , Mâle , Adulte d'âge moyen , Protéines à homéodomaine/génétique , Protéines à homéodomaine/métabolisme , Adulte , Tumeurs du cerveau/génétique , Tumeurs du cerveau/anatomopathologie , Tumeurs du cerveau/métabolisme , Tumeurs du cerveau/mortalité , Sujet âgéRÉSUMÉ
Objective: To study the clinicopathological features, immunohistochemical phenotypes, molecular changes, differential diagnosis and prognosis of isolated intraductal carcinoma of the prostate (iIDC-P). Methods: Three iIDC-P cases were collected retrospectively from 2016 to 2022 at Ningbo Clinical Pathology Diagnosis Center, Ningbo, China. The clinicopathologic features and immunophenotypic profiles were studied using light microscopy and immunohistochemistry. A targeted next-generation sequencing panel was used to analyze cancer-associated mutations. Follow-up and literature review were also performed. Results: The patients' ages were 61, 67 and 77 years, and their preoperative prostate specific antigen (PSA) levels were 7.99, 7.99 and 4.86 µg/L, respectively. Case 1 and 2 were diagnosed on needle biopsy and radical prostatectomy (RP) specimens, and case 3 was diagnosed on a specimen of transurethral resection of the prostate (TURP). The RP specimen was entirely submitted for histologic examination. In the case 1, iIDC-P was found in one tissue core (involving two ducts) in the biopsy specimen, and in 6 sections (diameter, 0.3-1.1 cm) from the radical prostatectomy specimen, and one section had separate foci of low-grade acinar adenocarcinoma (diameter, 0.05 cm). In the case 2, 6 tissue sections from the biopsy specimens showed iIDC-P, and 13 sections from RP specimen showed iIDC-P (diameter, 0.5-1.6 cm), and the other 3 sections had separate low grade acinar adenocarcinoma (diameter, 0.6 cm). In the case 3, 5 tissue blocks from the TURP specimen showed iIDC-P. The case 1 and 2 showed solid architecture with expansile proliferation of neoplastic cells in native ducts and acini. The case 3 showed dense or loose cribriform pattern, with marked cytological atypia, and frequent mitotic figures. Comedonecrosis was found in solid or dense cribriform glands in the case 2. Immunohistochemically, surrounding basal cells were highlighted using high-molecular-weight cytokeratin (34ßE12 and CK5/6) and p63, while P504s was positive in the tumor cells. The tumor cells were also positive for AR and prostate markers (NKX3.1, PSA and PSAP), and negative for GATA3. The iIDC-P and acinar adenocarcinoma both showed weak PTEN expression and no ERG (nuclear) expression. In case 2 and 3, targeted sequencing revealed activated oncogenic driver mutations in MAPK and PI3K pathway genes (KRAS, MTOR and PTEN). In addition, pathogenic mutation in TP53 and FOXA1 mutation were found in the case 2 and 3, respectively. No case demonstrated TMPRSS2::ERG translocation. All cases were microsatellite stable and had lower tumor mutation burdens (range, 2.1-3.1 muts/Mb). The patients showed no biochemical recurrence or metastasis after follow-up of 16-91 months. Conclusions: iIDC-P is a special type of intraductal carcinoma of the prostate and differs from intraductal carcinoma within high-grade prostate cancer. iIDC-P has unique molecular characteristics and may represent as a molecularly unique in situ tumor of prostate cancer.
Sujet(s)
Antigène spécifique de la prostate , Tumeurs de la prostate , Humains , Mâle , Tumeurs de la prostate/anatomopathologie , Tumeurs de la prostate/génétique , Tumeurs de la prostate/métabolisme , Tumeurs de la prostate/chirurgie , Sujet âgé , Adulte d'âge moyen , Études rétrospectives , Antigène spécifique de la prostate/métabolisme , Récepteurs aux androgènes/métabolisme , Récepteurs aux androgènes/génétique , Diagnostic différentiel , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Carcinome intracanalaire non infiltrant/anatomopathologie , Carcinome intracanalaire non infiltrant/génétique , Carcinome intracanalaire non infiltrant/métabolisme , Protéines à homéodomaine/métabolisme , Protéines à homéodomaine/génétique , Carcinome canalaire/anatomopathologie , Carcinome canalaire/génétique , Carcinome canalaire/métabolisme , Carcinome canalaire/chirurgie , Résection transuréthrale de prostate , Racémases et épimérases/métabolisme , Racémases et épimérases/génétique , Séquençage nucléotidique à haut débit , Pronostic , Kératines , Protéines membranairesRÉSUMÉ
Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients' response to antidepressant treatment.
Sujet(s)
Antidépresseurs , Cortex cérébral , Fluoxétine , Neurones GABAergiques , Protéines à homéodomaine , Récepteur trkB , Animaux , Neurones GABAergiques/métabolisme , Neurones GABAergiques/effets des médicaments et des substances chimiques , Protéines à homéodomaine/métabolisme , Protéines à homéodomaine/génétique , Fluoxétine/pharmacologie , Fluoxétine/usage thérapeutique , Souris , Antidépresseurs/pharmacologie , Antidépresseurs/usage thérapeutique , Cortex cérébral/effets des médicaments et des substances chimiques , Cortex cérébral/anatomopathologie , Cortex cérébral/métabolisme , Récepteur trkB/métabolisme , Récepteur trkB/génétique , Mâle , Transduction du signal/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Trouble dépressif majeur/traitement médicamenteux , Trouble dépressif majeur/métabolisme , Trouble dépressif majeur/anatomopathologie , Trouble dépressif majeur/génétiqueRÉSUMÉ
BACKGROUND: We conducted an investigation into the correlation between HOXA and associated long-noncoding RNAs, along with their clinicopathologic and prognostic features in non-small cell lung cancer (NSCLC). METHODS: A comprehensive search across multiple electronic databases, including PubMed and the Web of Science, was conducted to identify relevant studies. The association between HOXA, clinicopathologic parameters, and prognosis was assessed using relative risk (RR) and hazard ratio (HR) with a 95% confidence interval (CI). Data compilation was performed using STATA 12.0 software. RESULTS: A total of 11 trials involving 2058 patients with NSCLC were included in our study. Significant correlations were observed between HOXA-AS2 and TNM stage (III-IV) (RR=2.173, 95% CI: 1.386-5.437, P< 0.05) and HOTTIP and age (≥60-year-old) (RR=2.628, 95% CI: 1.185-5.829, P< 0.05) and non-smoking (RR=0.387, 95% CI: 0.156-0.959, P< 0.05). The combined results indicated a significant association between HOXA5 and increased overall survival (HRâ =â 0.69, 95% CIâ =â 0.57-0.84, Pâ <â .001). Additionally, HOXA-AS2, HOXA11 and HOTTIP were identified as potential independent predictors for poorer OS (HOXA-AS2: HR =3.48, 95% CI = 1.95 to 6.21, P < 0.05; HOXA11: HR=1.39, 95%CI = 1.08 to 1.79, P < 0.05; HOTTIP: HR=2.44, 95%CI = 1.10 to 5.42, P < 0.05). The prognostic significance of HOXA1, HOXA3 and HOXA4 was uncertain (HOXA1: HR=1.40, 95% CI =0.28 to 7.06, P > 0.05; HOXA3: HR=1.20, 95% CI = 0.96 to 1.50, P > 0.05; HOXA4: HR=0.97, 95% CI = 0.77 to 1.23, P > 0.05). CONCLUSIONS: The HOXA gene family has some potential to emerge as a novel prognostic factor for NSCLC and is correlated with some clinicopathological parameters such as the TNM stage, age and smoking. However, further meticulously designed prospective studies are warranted to substantiate these findings.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Protéines à homéodomaine , Tumeurs du poumon , ARN long non codant , Humains , ARN long non codant/génétique , Protéines à homéodomaine/génétique , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/mortalité , Pronostic , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/mortalité , Marqueurs biologiques tumoraux/génétique , Stadification tumoraleRÉSUMÉ
Branchio-oto-renal (BOR) and branchio-otic (BO) syndromes are characterized by anomalies affecting the ears, often accompanied by hearing loss, as well as abnormalities in the branchial arches and renal system. These syndromes exhibit a broad spectrum of phenotypes and a complex genomic landscape, with significant contributions from the EYA1 gene and the SIX gene family, including SIX1 and SIX5. Due to their diverse phenotypic presentations, which can overlap with other genetic syndromes, molecular genetic confirmation is essential. As sequencing technologies advance, whole-genome sequencing (WGS) is increasingly used in rare disease diagnostics. We explored the genomic landscape of 23 unrelated Korean families with typical or atypical BOR/BO syndrome using a stepwise approach: targeted panel sequencing and exome sequencing (Step 1), multiplex ligation-dependent probe amplification (MLPA) with copy number variation screening (Step 2), and WGS (Step 3). Integrating WGS into our diagnostic pipeline detected structure variations, including cryptic inversion and complex genomic rearrangement, eventually enhancing the diagnostic yield to 91%. Our findings expand the genomic architecture of BOR/BO syndrome and highlight the need for WGS to address the genetic diagnosis of clinically heterogeneous rare diseases.
Sujet(s)
Syndrome branchio-oto-rénal , Variations de nombre de copies de segment d'ADN , Séquençage du génome entier , Humains , Syndrome branchio-oto-rénal/génétique , République de Corée , Séquençage du génome entier/méthodes , Femelle , Mâle , Variations de nombre de copies de segment d'ADN/génétique , Protéines et peptides de signalisation intracellulaire/génétique , Maladies rares/génétique , Protéines nucléaires/génétique , Protéines à homéodomaine/génétique , Enfant , Protein Tyrosine Phosphatases/génétique , Enfant d'âge préscolaire , Adulte , Génomique/méthodes , Phénotype , Pedigree , Adolescent , NourrissonRÉSUMÉ
Endometrial cancer (UCEC) is one of three major malignant tumors in women. The HOX gene regulates tumor development. However, the potential roles of HOX in the expression mechanism of multiple cell types and in the development and progression of tumor microenvironment (TME) cell infiltration in UCEC remain unknown. In this study, we utilized both the The Cancer Genome Atlas (TCGA) database and International Cancer Genome Consortium (ICGC) database to analyze transcriptome data of 529 patients with UCEC based on 39 HOX genes, combing clinical information, we discovered HOX gene were a pivotal factor in the development and progression of UCEC and in the formation of TME diversity and complexity. Here, a new scoring system was developed to quantify individual HOX patterns in UCEC. Our study found that patients in the low HOX score group had abundant anti-tumor immune cell infiltration, good tumor differentiation, and better prognoses. In contrast, a high HOX score was associated with blockade of immune checkpoints, which enhances the response to immunotherapy. The Real-Time quantitative PCR (RT-qPCR) and Immunohistochemistry (IHC) exhibited a higher expression of the HOX gene in the tumor patients. We revealed that the significant upregulation of the HOX gene in the epithelial cells can activate signaling pathway associated with tumour invasion and metastasis through single-cell RNA sequencing (scRNA-seq), such as nucleotide metabolic proce and so on. Finally, a risk prognostic model established by the positive relationship between HOX scores and cancer-associated fibroblasts (CAFs) can predict the prognosis of individual patients by scRNA-seq and transcriptome data sets. In sum, HOX gene may serve as a potential biomarker for the diagnosis and prediction of UCEC and to develop more effective therapeutic strategies.
Sujet(s)
Tumeurs de l'endomètre , Régulation de l'expression des gènes tumoraux , Microenvironnement tumoral , Humains , Tumeurs de l'endomètre/génétique , Tumeurs de l'endomètre/immunologie , Tumeurs de l'endomètre/anatomopathologie , Femelle , Microenvironnement tumoral/immunologie , Microenvironnement tumoral/génétique , Pronostic , Protéines à homéodomaine/génétique , Protéines à homéodomaine/métabolisme , Transcriptome , Gènes homéotiques/génétique , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Bases de données génétiques , Analyse de profil d'expression de gènes , Adulte d'âge moyenRÉSUMÉ
Transcription factors specifically bind to their consensus sequence motifs and regulate transcription efficiency. Transcription factors are also able to non-specifically contact the phosphate backbone of DNA through electrostatic interaction. The homeodomain of Meis1 TALE human transcription factor (Meis1-HD) recognizes its target DNA sequences via two DNA contact regions, the L1-α1 region and the α3 helix (specific binding mode). This study demonstrates that the non-specific binding mode of Meis1-HD is the energetically favored process during DNA binding, achieved by the interaction of the L1-α1 region with the phosphate backbone. An NMR dynamics study suggests that non-specific binding might set up an intermediate structure which can then rapidly and easily find the consensus region on a long section of genomic DNA in a facilitated binding process. Structural analysis using NMR and molecular dynamics shows that key structural distortions in the Meis1-HD-DNA complex are induced by various single nucleotide mutations in the consensus sequence, resulting in decreased DNA binding affinity. Collectively, our results elucidate the detailed molecular mechanism of how Meis1-HD recognizes single nucleotide mutations within its consensus sequence: (i) through the conformational features of the α3 helix; and (ii) by the dynamic features (rigid or flexible) of the L1 loop and the α3 helix. These findings enhance our understanding of how single nucleotide mutations in transcription factor consensus sequences lead to dysfunctional transcription and, ultimately, human disease.
Sujet(s)
ADN , Simulation de dynamique moléculaire , Protéine du site-1 d'intégration des virus myéloïdes écotropiques , Liaison aux protéines , Protéine du site-1 d'intégration des virus myéloïdes écotropiques/métabolisme , Protéine du site-1 d'intégration des virus myéloïdes écotropiques/génétique , Humains , ADN/métabolisme , ADN/composition chimique , ADN/génétique , Sites de fixation , Protéines à homéodomaine/métabolisme , Protéines à homéodomaine/génétique , Protéines à homéodomaine/composition chimique , Mutation , Séquence consensus , Séquence nucléotidiqueRÉSUMÉ
Aim: Type II diabetes (T2D) stems from insulin resistance, with ß-cell dysfunction as a hallmark in its progression. Studies reveal that ß cells undergo apoptosis or dedifferentiation during T2D development. The transcription factor PAX4 is vital for ß differentiation and survival, thus may be a potential enhancer of ß-cell function in T2D islets. Materials & methods: Human PAX4 cDNA was delivered into T2D human islets with an adenoviral vector, and its effects on ß cells were examined. Results: PAX4 gene delivery significantly improved ß-cell survival, and increased ß-cell composition in the T2D human islets. Basal insulin and glucose-stimulated insulin secretion in PAX4-expressing islets were substantially higher than untreated or control-treated T2D human islets. Conclusion: Introduced PAX4 expression in T2D human islets improves ß-cell function, thus could provide therapeutic benefits for T2D treatment.
Type II diabetes (T2D) results from insulin resistance, with ß-cell dysfunction playing a pivotal role in its progression. Deficits in ß-cell mass and function have been attributed primarily to ß-cell death through apoptosis; however, recent studies suggest ß-cell failure can also arise from ß-cell dedifferentiation that is, ß cells undergo a loss of mature identity, adopting either progenitor-like or glucagon-producing α cell states during T2D development. Therefore, a strategy preventing ß-cell dedifferentiation while promoting its survival is beneficial for T2D treatment. In this study, we explored whether PAX4, a critical transcription factor for ß differentiation and survival, could alleviate ß-cell dysfunction in human islets derived from T2D patients. To accomplish that, human PAX4 cDNA was delivered into human islets isolated from T2D donors by an adenoviral vector-based vector, Ad5.Pax4 and its effects on ß-cell function were evaluated. The results showed PAX4 expression significantly improved ß-cell survival and increased ß-cell composition in the T2D islets. Notably, PAX4-treated T2D islets exhibited significantly higher basal insulin secretion and glucose-stimulated insulin secretion than control-treated islets. The data demonstrate that PAX4 gene delivery into T2D human islets enhances ß-cell mass and function, and thus may offer therapeutic benefits in the treatment of T2D.
Sujet(s)
Diabète de type 2 , Protéines à homéodomaine , Cellules à insuline , Insuline , Facteurs de transcription PAX , Humains , Diabète de type 2/thérapie , Diabète de type 2/génétique , Diabète de type 2/métabolisme , Facteurs de transcription PAX/métabolisme , Facteurs de transcription PAX/génétique , Cellules à insuline/métabolisme , Protéines à homéodomaine/génétique , Protéines à homéodomaine/métabolisme , Insuline/métabolisme , Sécrétion d'insuline , Techniques de transfert de gènes , Survie cellulaire , Ilots pancréatiques/métabolisme , Thérapie génétique/méthodesRÉSUMÉ
Plants flower in response to environmental signals. These signals change the shape and developmental identity of the shoot apical meristem (SAM), causing it to form flowers and inflorescences. We show that the increases in SAM width and height during floral transition correlate with changes in size of the central zone (CZ), defined by CLAVATA3 expression, and involve a transient increase in the height of the organizing center (OC), defined by WUSCHEL expression. The APETALA2 (AP2) transcription factor is required for the rapid increases in SAM height and width, by maintaining the width of the OC and increasing the height and width of the CZ. AP2 expression is repressed in the SAM at the end of floral transition, and extending the duration of its expression increases SAM width. Transcriptional repression by SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) represents one of the mechanisms reducing AP2 expression during floral transition. Moreover, AP2 represses SOC1 transcription, and we find that reciprocal repression of SOC1 and AP2 contributes to synchronizing precise changes in meristem shape with floral transition.
Sujet(s)
Protéines d'Arabidopsis , Arabidopsis , Fleurs , Régulation de l'expression des gènes végétaux , Protéines à homéodomaine , Protéines à domaine MADS , Méristème , Arabidopsis/génétique , Arabidopsis/métabolisme , Arabidopsis/croissance et développement , Méristème/métabolisme , Méristème/croissance et développement , Méristème/génétique , Protéines d'Arabidopsis/métabolisme , Protéines d'Arabidopsis/génétique , Fleurs/génétique , Fleurs/croissance et développement , Fleurs/métabolisme , Protéines à homéodomaine/métabolisme , Protéines à homéodomaine/génétique , Protéines à domaine MADS/métabolisme , Protéines à domaine MADS/génétique , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Régulation de l'expression des gènes au cours du développement , Végétaux génétiquement modifiésRÉSUMÉ
BACKGROUND: Early gastric cancer is treated endoscopically, but patients require surveillance due to the risk of metachronous gastric lesions (MGLs). Epigenetic alterations, particularly aberrant DNA methylation in genes, such as MIR124-3, MIR34b/c, NKX6-1, EMX1, MOS and CDO1, have been identified as promising biomarkers for MGL in Asian populations. We aimed to determine whether these changes could predict MGL risk in intermediate-risk Caucasian patients. METHODS: This case-cohort study included 36 patients who developed MGL matched to 48 patients without evidence of MGL in the same time frame (controls). Multiplex quantitative methylation-specific PCR was performed using DNA extracted from the normal mucosa adjacent to the primary lesion. The overall risk of progression to MGL was assessed using Kaplan-Meier and Cox proportional hazards model analyses. RESULTS: MIR124-3, MIR34b/c and NKX6-1 were successfully analyzed in 77 samples. MIR124-3 hypermethylation was detected in individuals who developed MGL (relative quantification 78.8 vs 50.5 in controls, p = 0.014), particularly in females and Helicobacter pylori-negative patients (p = 0.021 and p = 0.0079, respectively). This finding was further associated with a significantly greater risk for MGL development (aHR = 2.31, 95% CI 1.03-5.17, p = 0.042). Similarly, NKX6-1 was found to be hypermethylated in patients with synchronous lesions (relative quantification 7.9 vs 0.0 in controls, p = 0.0026). A molecular-based methylation model incorporating both genes was significantly associated with a threefold increased risk for MGL development (aHR = 3.10, 95% CI 1.07-8.95, p = 0.037). CONCLUSIONS: This preliminary study revealed an association between MIR124-3 and NKX6-1 hypermethylation and the development of MGL in a Western population. These findings may represent a burden reduction and a greener approach to patient care.
Sujet(s)
Méthylation de l'ADN , Protéines à homéodomaine , microARN , Tumeurs de l'estomac , Humains , Femelle , Mâle , microARN/génétique , Tumeurs de l'estomac/génétique , Méthylation de l'ADN/génétique , Adulte d'âge moyen , Sujet âgé , Protéines à homéodomaine/génétique , /génétique , Études cas-témoins , Seconde tumeur primitive/génétique , Épigenèse génétique/génétique , Marqueurs biologiques tumoraux/génétiqueRÉSUMÉ
Animal body plans are established during embryonic development by the Hox genes. This patterning process relies on the differential expression of Hox genes along the head-to-tail axis. Hox spatial collinearity refers to the relationship between the organization of Hox genes in clusters and the differential Hox expression, whereby the relative order of the Hox genes within a cluster mirrors the spatial sequence of expression in the developing embryo. In vertebrates, the cluster organization is also associated with the timing of Hox activation, which harmonizes Hox expression with the progressive emergence of axial tissues. Thereby, in vertebrates, Hox temporal collinearity is intimately linked to Hox spatial collinearity. Understanding the mechanisms contributing to Hox temporal and spatial collinearity is thus key to the comprehension of vertebrate patterning. Here, we provide an overview of the main discoveries pertaining to the mechanisms of Hox spatial-temporal collinearity.
Sujet(s)
Plan d'organisation du corps , Régulation de l'expression des gènes au cours du développement , Gènes homéotiques , Protéines à homéodomaine , Vertébrés , Animaux , Vertébrés/génétique , Gènes homéotiques/génétique , Plan d'organisation du corps/génétique , Protéines à homéodomaine/métabolisme , Protéines à homéodomaine/génétique , Développement embryonnaire/génétique , Famille multigéniqueRÉSUMÉ
Lung cancer is a leading cause of cancer death worldwide, with high incidence and poor survival rates. Cold atmospheric plasma (CAP) technology has emerged as a promising therapeutic approach for cancer treatment, inducing oxidative stress in malignant tissues without causing thermal damage. However, the role of CAP in regulating lung cancer cell ferroptosis remains unclear. Here, we observed that CAP effectively suppressed the growth and migration abilities of lung cancer cells, with significantly increased ferroptotic cell death, lipid peroxidation, and decreased mitochondrial membrane potential. Mechanistically, CAP regulates SLC7A11-mediated cell ferroptosis by modulating HOXB9. SLC7A11, a potent ferroptosis suppressor, was markedly reduced by HOXB9 knockdown, while it was enhanced by overexpressing HOXB9. The luciferase and ChIP assays confirmed that HOXB9 can directly target SLC7A11 and regulate its gene transcription. Additionally, CAP enhanced the acetylation modification level of HOXB9 by promoting its interaction with acetyltransferase p300/CBP-associated factor (PCAF). Acetylated HOXB9 affects its protein ubiquitination modification level, which in turn affects its protein stability. Notably, the upregulation of SLC7A11 and HOXB9 mitigated the suppressive effects of CAP on ferroptosis status, cell proliferation, invasion, and migration in lung cancer cells. Furthermore, animal models have also confirmed that CAP can inhibit the progression of lung cancer in vivo. Overall, this study highlights the significance of the downregulation of the HOXB9/SLC7A11 axis by CAP treatment in inhibiting lung cancer, offering novel insights into the potential mechanisms and therapeutic strategies of CAP for lung cancer.
Sujet(s)
Système y+ de transport d'acides aminés , Carcinome pulmonaire non à petites cellules , Ferroptose , Régulation de l'expression des gènes tumoraux , Protéines à homéodomaine , Tumeurs du poumon , Facteurs de transcription CBP-p300 , Humains , Système y+ de transport d'acides aminés/métabolisme , Système y+ de transport d'acides aminés/génétique , Carcinome pulmonaire non à petites cellules/métabolisme , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/génétique , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/génétique , Acétylation , Facteurs de transcription CBP-p300/métabolisme , Animaux , Souris , Protéines à homéodomaine/métabolisme , Protéines à homéodomaine/génétique , Lignée cellulaire tumorale , Prolifération cellulaire , Mouvement cellulaireRÉSUMÉ
The coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic islet-dependent glucose homeostasis. In this study we carried out a comprehensive assessment of metabolic alterations in Alx3 deficiency. We report that Alx3-deficient mice exhibit decreased food intake without changes in body weight, along with reduced energy expenditure and altered respiratory exchange ratio. Magnetic resonance imaging reveals increased adiposity and decreased muscle mass, which was associated with markers of motor and sympathetic denervation. By contrast, Alx3-deficient mice on a high-fat diet show attenuated weight gain and improved insulin sensitivity, compared to control mice. Gene expression analysis demonstrates altered lipogenic and lipolytic gene profiles. In wild type mice Alx3 is expressed in hypothalamic arcuate nucleus neurons, but not in major peripheral metabolic organs. Functional diffusion-weighted magnetic resonance imaging reveals selective hypothalamic responses to fasting in the arcuate nucleus of Alx3-deficient mice. Additionally, altered expression of proopiomelanocortin and melanocortin-3 receptor mRNA in the hypothalamus suggests impaired regulation of feeding behavior. This study highlights the crucial role for Alx3 in governing food intake, energy homeostasis, and metabolic nutrient partitioning, thereby influencing body mass composition.
Sujet(s)
Composition corporelle , Consommation alimentaire , Métabolisme énergétique , Protéines à homéodomaine , Homéostasie , Hypothalamus , Souris knockout , Animaux , Métabolisme énergétique/génétique , Hypothalamus/métabolisme , Souris , Consommation alimentaire/génétique , Protéines à homéodomaine/génétique , Protéines à homéodomaine/métabolisme , Alimentation riche en graisse , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Mâle , Souris de lignée C57BL , Neurones/métabolisme , Pro-opiomélanocortine/métabolisme , Pro-opiomélanocortine/génétique , Insulinorésistance/génétique , Noyau arqué de l'hypothalamus/métabolismeRÉSUMÉ
Mesenchymal stromal cell (MSC) senescence is a key factor in skeletal aging, affecting the potential of MSC applications. Identifying targets to prevent MSC and skeletal senescence is crucial. Here, we report increased miR-29 expression in bone tissues of aged mice, osteoporotic patients, and senescent MSCs. Genetic overexpression of miR-29 in Prx1-positive MSCs significantly accelerates skeletal senescence, reducing cortical bone thickness and trabecular bone mass, while increasing femur cross-sectional area, bone marrow adiposity, p53, and senescence-associated secretory phenotype (SASP) levels. Mechanistically, miR-29 promotes senescence by upregulating p53 via targeting Kindlin-2 mRNA. miR-29 knockdown in BMSCs impedes skeletal senescence, enhances bone mass, and accelerates calvarial defect regeneration, also reducing lipopolysaccharide (LPS)-induced organ injuries and mortality. Thus, our findings underscore miR-29 as a promising therapeutic target for senescence-related skeletal diseases and acute inflammation-induced organ damage.