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The circadian clock system coordinates metabolic, physiological, and behavioral functions across a 24-h cycle, crucial for adapting to environmental changes. Disruptions in circadian rhythms contribute to major metabolic pathologies like obesity and Type 2 diabetes. Understanding the regulatory mechanisms governing circadian control is vital for identifying therapeutic targets. It is well characterized that chromatin remodeling and 3D structure at genome regulatory elements contributes to circadian transcriptional cycles; yet the impact of rhythmic chromatin topology in metabolic disease is largely unexplored. In this study, we explore how the spatial configuration of the genome adapts to diet, rewiring circadian transcription and contributing to dysfunctional metabolism. We describe daily fluctuations in chromatin contacts between distal regulatory elements of metabolic control genes in livers from lean and obese mice and identify specific lipid-responsive regions recruiting the clock molecular machinery. Interestingly, under high-fat feeding, a distinct interactome for the clock-controlled gene Dbp strategically promotes the expression of distal metabolic genes including Fgf21. Alongside, new chromatin loops between regulatory elements from genes involved in lipid metabolism control contribute to their transcriptional activation. These enhancers are responsive to lipids through CEBPß, counteracting the circadian repressor REVERBa. Our findings highlight the intricate coupling of circadian gene expression to a dynamic nuclear environment under high-fat feeding, supporting a temporally regulated program of gene expression and transcriptional adaptation to diet.
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Cromatina , Relógios Circadianos , Ácidos Graxos , Fígado , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade , Animais , Cromatina/metabolismo , Cromatina/genética , Fígado/metabolismo , Camundongos , Relógios Circadianos/genética , Obesidade/metabolismo , Obesidade/genética , Ácidos Graxos/metabolismo , Masculino , Dieta Hiperlipídica/efeitos adversos , Montagem e Desmontagem da Cromatina , Ritmo Circadiano/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Metabolismo dos Lipídeos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Breast cancer, characterized by its complexity and diversity, presents significant challenges in understanding its underlying biology. In this study, we employed gene co-expression network analysis to investigate the gene composition and functional patterns in breast cancer subtypes and normal breast tissue. Our objective was to elucidate the detailed immunological features distinguishing these tumors at the transcriptional level and to explore their implications for diagnosis and treatment. The analysis identified nine distinct gene module clusters, each representing unique transcriptional signatures within breast cancer subtypes and normal tissue. Interestingly, while some clusters exhibited high similarity in gene composition between normal tissue and certain subtypes, others showed lower similarity and shared traits. These clusters provided insights into the immune responses within breast cancer subtypes, revealing diverse immunological functions, including innate and adaptive immune responses. Our findings contribute to a deeper understanding of the molecular mechanisms underlying breast cancer subtypes and highlight their unique characteristics. The immunological signatures identified in this study hold potential implications for diagnostic and therapeutic strategies. Additionally, the network-based approach introduced herein presents a valuable framework for understanding the complexities of other diseases and elucidating their underlying biology.
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Neoplasias da Mama , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Inflamação , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Feminino , Inflamação/imunologia , Inflamação/genética , Transcriptoma , Biomarcadores Tumorais/genéticaRESUMO
It has been documented that variations in glycosylation on glycoprotein hormones, confer distinctly different biological features to the corresponding glycoforms when multiple in vitro biochemical readings are analyzed. We here applied next generation RNA sequencing to explore changes in the transcriptome of rat granulosa cells exposed for 0, 6, and 12 h to 100 ng/ml of four highly purified follicle-stimulating hormone (FSH) glycoforms, each exhibiting different glycosylation patterns: a. human pituitary FSH18/21 (hypo-glycosylated); b. human pituitary FSH24 (fully glycosylated); c. Equine FSH (eqFSH) (hypo-glycosylated); and d. Chinese-hamster ovary cell-derived human recombinant FSH (recFSH) (fully-glycosylated). Total RNA from triplicate incubations was prepared from FSH glycoform-exposed cultured granulosa cells obtained from DES-pretreated immature female rats, and RNA libraries were sequenced in a HighSeq 2500 sequencer (2 x 125 bp paired-end format, 10-15 x 106 reads/sample). The computational workflow focused on investigating differences among the four FSH glycoforms at three levels: gene expression, enriched biological processes, and perturbed pathways. Among the top 200 differentially expressed genes, only 4 (0.6%) were shared by all 4 glycoforms at 6 h, whereas 118 genes (40%) were shared at 12 h. Follicle-stimulating hormone glycocoforms stimulated different patterns of exclusive and associated up regulated biological processes in a glycoform and time-dependent fashion with more shared biological processes after 12 h of exposure and fewer treatment-specific ones, except for recFSH, which exhibited stronger responses with more specifically associated processes at this time. Similar results were found for down-regulated processes, with a greater number of processes at 6 h or 12 h, depending on the particular glycoform. In general, there were fewer downregulated than upregulated processes at both 6 h and 12 h, with FSH18/21 exhibiting the largest number of down-regulated associated processes at 6 h while eqFSH exhibited the greatest number at 12 h. Signaling cascades, largely linked to cAMP-PKA, MAPK, and PI3/AKT pathways were detected as differentially activated by the glycoforms, with each glycoform exhibiting its own molecular signature. These data extend previous observations demonstrating glycosylation-dependent distinctly different regulation of gene expression and intracellular signaling pathways triggered by FSH in granulosa cells. The results also suggest the importance of individual FSH glycoform glycosylation for the conformation of the ligand-receptor complex and induced signalling pathways.
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Hormônio Foliculoestimulante , Células da Granulosa , Transcriptoma , Animais , Feminino , Células da Granulosa/metabolismo , Células da Granulosa/efeitos dos fármacos , Hormônio Foliculoestimulante/farmacologia , Hormônio Foliculoestimulante/metabolismo , Ratos , Glicosilação , Transcriptoma/efeitos dos fármacos , Humanos , Células Cultivadas , RNA-Seq/métodos , Células CHO , CricetulusRESUMO
This study investigated the relationship between Metabolic Syndrome (MetS), sleep disorders, the consumption of some nutrients, and social development factors, focusing on gender differences in an unbalanced dataset from a Mexico City cohort. We used data balancing techniques like SMOTE and ADASYN after employing machine learning models like random forest and RPART to predict MetS. Random forest excelled, achieving significant, balanced accuracy, indicating its robustness in predicting MetS and achieving a balanced accuracy of approximately 87%. Key predictors for men included body mass index and family history of gout, while waist circumference and glucose levels were most significant for women. In relation to diet, sleep quality, and social development, metabolic syndrome in men was associated with high lactose and carbohydrate intake, educational lag, living with a partner without marrying, and lack of durable goods, whereas in women, best predictors in these dimensions include protein, fructose, and cholesterol intake, copper metabolites, snoring, sobbing, drowsiness, sanitary adequacy, and anxiety. These findings underscore the need for personalized approaches in managing MetS and point to a promising direction for future research into the interplay between social factors, sleep disorders, and metabolic health, which mainly depend on nutrient consumption by region.
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Síndrome Metabólica , Transtornos do Sono-Vigília , Masculino , Humanos , Feminino , Síndrome Metabólica/complicações , Qualidade do Sono , Mudança Social , Ingestão de Alimentos , Circunferência da Cintura , Índice de Massa Corporal , Transtornos do Sono-Vigília/complicações , Aprendizado de Máquina , Fatores de RiscoRESUMO
Lung tumors are a leading cause of cancer-related death worldwide. Lung cancers are highly heterogeneous on their phenotypes, both at the cellular and molecular levels. Efforts to better understand the biological origins and outcomes of lung cancer in terms of this enormous variability often require of high-throughput experimental techniques paired with advanced data analytics. Anticipated advancements in multi-omic methodologies hold potential to reveal a broader molecular perspective of these tumors. This study introduces a theoretical and computational framework for generating network models depicting regulatory constraints on biological functions in a semi-automated way. The approach successfully identifies enriched functions in analyzed omics data, focusing on Adenocarcinoma (LUAD) and Squamous cell carcinoma (LUSC, a type of NSCLC) in the lung. Valuable information about novel regulatory characteristics, supported by robust biological reasoning, is illustrated, for instance by considering the role of genes, miRNAs and CpG sites associated with NSCLC, both novel and previously reported. Utilizing multi-omic regulatory networks, we constructed robust models elucidating omics data interconnectedness, enabling systematic generation of mechanistic hypotheses. These findings offer insights into complex regulatory mechanisms underlying these cancer types, paving the way for further exploring their molecular complexity.
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Cardiovascular diseases stand as a prominent global cause of mortality, their intricate origins often entwined with comorbidities and multimorbid conditions. Acknowledging the pivotal roles of age, sex, and social determinants of health in shaping the onset and progression of these diseases, our study delves into the nuanced interplay between life-stage, socioeconomic status, and comorbidity patterns within cardiovascular diseases. Leveraging data from a cross-sectional survey encompassing Mexican adults, we unearth a robust association between these variables and the prevalence of comorbidities linked to cardiovascular conditions. To foster a comprehensive understanding of multimorbidity patterns across diverse life-stages, we scrutinize an extensive dataset comprising 47,377 cases diagnosed with cardiovascular ailments at Mexico's national reference hospital. Extracting sociodemographic details, primary diagnoses prompting hospitalization, and additional conditions identified through ICD-10 codes, we unveil subtle yet significant associations and discuss pertinent specific cases. Our results underscore a noteworthy trend: younger patients of lower socioeconomic status exhibit a heightened likelihood of cardiovascular comorbidities compared to their older counterparts with a higher socioeconomic status. By empowering clinicians to discern non-evident comorbidities, our study aims to refine therapeutic designs. These findings offer profound insights into the intricate interplay among life-stage, socioeconomic status, and comorbidity patterns within cardiovascular diseases. Armed with data-supported approaches that account for these factors, clinical practices stand to be enhanced, and public health policies informed, ultimately advancing the prevention and management of cardiovascular disease in Mexico.
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Topological data analysis (TDA) is a recent approach for analyzing and interpreting complex data sets based on ideas a branch of mathematics called algebraic topology. TDA has proven useful to disentangle non-trivial data structures in a broad range of data analytics problems including the study of cardiovascular signals. Here, we aim to provide an overview of the application of TDA to cardiovascular signals and its potential to enhance the understanding of cardiovascular diseases and their treatment in the form of a literature or narrative review. We first introduce the concept of TDA and its key techniques, including persistent homology, Mapper, and multidimensional scaling. We then discuss the use of TDA in analyzing various cardiovascular signals, including electrocardiography, photoplethysmography, and arterial stiffness. We also discuss the potential of TDA to improve the diagnosis and prognosis of cardiovascular diseases, as well as its limitations and challenges. Finally, we outline future directions for the use of TDA in cardiovascular signal analysis and its potential impact on clinical practice. Overall, TDA shows great promise as a powerful tool for the analysis of complex cardiovascular signals and may offer significant insights into the understanding and management of cardiovascular diseases.
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Breast cancer encompasses a diverse array of subtypes, each exhibiting distinct clinical characteristics and treatment responses. Unraveling the underlying regulatory mechanisms that govern gene expression patterns in these subtypes is essential for advancing our understanding of breast cancer biology. Gene co-expression networks (GCNs) help us identify groups of genes that work in coordination. Previous research has revealed a marked reduction in the interaction of genes located on different chromosomes within GCNs for breast cancer, as well as for lung, kidney, and hematopoietic cancers. However, the reasons behind why genes on the same chromosome often co-express remain unclear. In this study, we investigate the role of transcription factors in shaping gene co-expression networks within the four main breast cancer subtypes: Luminal A, Luminal B, HER2+, and Basal, along with normal breast tissue. We identify communities within each GCN and calculate the transcription factors that may regulate these communities, comparing the results across different phenotypes. Our findings indicate that, in general, regulatory behavior is to a large extent similar among breast cancer molecular subtypes and even in healthy networks. This suggests that transcription factor motif usage does not fully determine long-range co-expression patterns. Specific transcription factor motifs, such as CCGGAAG, appear frequently across all phenotypes, even involving multiple highly connected transcription factors. Additionally, certain transcription factors exhibit unique actions in specific subtypes but with limited influence. Our research demonstrates that the loss of inter-chromosomal co-expression is not solely attributable to transcription factor regulation. Although the exact mechanism responsible for this phenomenon remains elusive, this work contributes to a better understanding of gene expression regulatory programs in breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Fatores de Transcrição/genética , Mama , Cromossomos , Regulação Neoplásica da Expressão GênicaRESUMO
Introduction: The COVID-19 pandemic, especially its early stages, sparked extensive discussions regarding the potential impact of metabolic and cardiovascular comorbidities on the severity and fatality of SARS-CoV-2 infection, yielding inconclusive outcomes. In this study, we delve into the prevalence of metabolic and cardiovascular comorbidities within COVID-19 patients in Mexico. Methods: Employing a retrospective observational study design, we collected data from official databases encompassing COVID-19 patients admitted to both public and private hospitals in Mexico City. Results: Our investigation unveiled a noteworthy incongruity in the prevalence of metabolic and cardiovascular comorbidities among COVID-19 patients, with a particular emphasis on obesity, hypertension, and diabetes. This incongruity manifests as location-dependent phenomena, where the prevalence of these comorbidities among COVID-19 patients significantly deviates from the reported values for the general population in each specific location. Discussion: These findings underscore the critical importance of screening for metabolic and cardiovascular comorbidities in COVID-19 patients and advocate for the necessity of tailored interventions for this specific population. Furthermore, our study offers insights into the intricate interplay between COVID-19 and metabolic and cardiovascular comorbidities, serving as a valuable foundation for future research endeavors and informing clinical practice.
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COVID-19 , Pandemias , Humanos , Comorbidade , COVID-19/epidemiologia , México/epidemiologia , SARS-CoV-2 , Estudos RetrospectivosRESUMO
Single cell computational analysis has emerged as a powerful tool in the field of oncology, enabling researchers to decipher the complex cellular heterogeneity that characterizes cancer. By leveraging computational algorithms and bioinformatics approaches, this methodology provides insights into the underlying genetic, epigenetic and transcriptomic variations among individual cancer cells. In this paper, we present a comprehensive overview of single cell computational analysis in oncology, discussing the key computational techniques employed for data processing, analysis, and interpretation. We explore the challenges associated with single cell data, including data quality control, normalization, dimensionality reduction, clustering, and trajectory inference. Furthermore, we highlight the applications of single cell computational analysis, including the identification of novel cell states, the characterization of tumor subtypes, the discovery of biomarkers, and the prediction of therapy response. Finally, we address the future directions and potential advancements in the field, including the development of machine learning and deep learning approaches for single cell analysis. Overall, this paper aims to provide a roadmap for researchers interested in leveraging computational methods to unlock the full potential of single cell analysis in understanding cancer biology with the goal of advancing precision oncology. For this purpose, we also include a notebook that instructs on how to apply the recommended tools in the Preprocessing and Quality Control section.