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Bioinformatics ; 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35040932


MOTIVATION: Alzheimer's disease (AD) is a complex brain disorder with risk genes incompletely identified. The candidate genes are dominantly obtained by computational approaches. In order to obtain biological insights of candidate genes or screen genes for experimental testing, it is essential to assess their relevance to AD. A platform that integrates different types of omics data and approaches would facilitate the analysis of candidate genes and is in great need. RESULTS: We report AlzCode, a platform for multiview analysis of genes related to AD. First, this platform integrates a rich collection of functional genomic data, including expression data of AD samples (gene expression, single-cell RNA-seq data, and protein expression), AD-specific biological networks (co-expression networks and functional gene networks), neuropathological and clinical traits (CERAD score, Braak staging score, Clinical Dementia Rating, cognitive function, and clinical severity), as well as general data such as protein-protein interaction, regulatory networks, sequence similarity and miRNA-target interactions. These data provide basis for analyzing genes from different views. Second, the platform integrates multiple approaches designed for the various types of data. We implement functions to analyze both individual genes and gene sets. We also compare AlzCode with two existing platforms for AD analysis, which are Agora and AD Altas. We pinpoint the features of each platform and highlight their differences. This platform would be valuable to the understanding of AD genetics and pathological mechanisms. AVAILABILITY AND IMPLEMENTATION: AlzCode is freely available at: SUPPLEMENTARY INFORMATION: Supplementary data is available at Bioinformatics online.

Brief Bioinform ; 23(1)2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-34953465


Alzheimer's disease (AD) has a strong genetic predisposition. However, its risk genes remain incompletely identified. We developed an Alzheimer's brain gene network-based approach to predict AD-associated genes by leveraging the functional pattern of known AD-associated genes. Our constructed network outperformed existing networks in predicting AD genes. We then systematically validated the predictions using independent genetic, transcriptomic, proteomic data, neuropathological and clinical data. First, top-ranked genes were enriched in AD-associated pathways. Second, using external gene expression data from the Mount Sinai Brain Bank study, we found that the top-ranked genes were significantly associated with neuropathological and clinical traits, including the Consortium to Establish a Registry for Alzheimer's Disease score, Braak stage score and clinical dementia rating. The analysis of Alzheimer's brain single-cell RNA-seq data revealed cell-type-specific association of predicted genes with early pathology of AD. Third, by interrogating proteomic data in the Religious Orders Study and Memory and Aging Project and Baltimore Longitudinal Study of Aging studies, we observed a significant association of protein expression level with cognitive function and AD clinical severity. The network, method and predictions could become a valuable resource to advance the identification of risk genes for AD.

Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Redes Reguladoras de Genes , Predisposição Genética para Doença , Envelhecimento/genética , Perfilação da Expressão Gênica , Humanos , Estudos Longitudinais , Memória , Proteômica , RNA-Seq , Transcriptoma
Int J Mol Sci ; 22(18)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34576009


The bone morphogenetic protein (Bmp) signaling pathway and the basic helix-loop-helix (bHLH) transcription factor Hand1 are known key regulators of cardiac development. In this study, we investigated the Bmp signaling regulation of Hand1 during cardiac outflow tract (OFT) development. In Bmp2 and Bmp4loss-of-function embryos with varying levels of Bmp in the heart, Hand1 is sensitively decreased in response to the dose of Bmp expression. In contrast, Hand1 in the heart is dramatically increased in Bmp4 gain-of-function embryos. We further identified and characterized the Bmp/Smad regulatory elements in Hand1. Combined transfection assays and chromatin immunoprecipitation (ChIP) experiments indicated that Hand1 is directly activated and bound by Smads. In addition, we found that upon the treatment of Bmp2 and Bmp4, P19 cells induced Hand1 expression and favored cardiac differentiation. Together, our data indicated that the Bmp signaling pathway directly regulates Hand1 expression in a dose-dependent manner during heart development.

Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Embrião de Mamíferos/embriologia , Coração/embriologia , Organogênese , Transdução de Sinais , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 4/genética , Camundongos , Camundongos Knockout
J Vis Exp ; (174)2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34459809


Neural crest cells (NCCs) are vertebrate embryonic multipotent cells that can migrate and differentiate into a wide array of cell types that give rise to various organs and tissues. Tissue stiffness produces mechanical force, a physical cue that plays a critical role in NCC differentiation; however, the mechanism remains unclear. The method described here provides detailed information for the optimized generation of polyacrylamide hydrogels of varying stiffness, the accurate measurement of such stiffness, and the evaluation of the impact of mechanical signals in O9-1 cells, a NCC line that mimics in vivo NCCs. Hydrogel stiffness was measured using atomic force microscopy (AFM) and indicated different stiffness levels accordingly. O9-1 NCCs cultured on hydrogels of varying stiffness showed different cell morphology and gene expression of stress fibers, which indicated varying biological effects caused by mechanical signal changes. Moreover, this established that varying the hydrogel stiffness resulted in an efficient in vitro system to manipulate mechanical signaling by altering gel stiffness and analyzing the molecular and genetic regulation in NCCs. O9-1 NCCs can differentiate into a wide range of cell types under the influence of the corresponding differentiation media, and it is convenient to manipulate chemical signals in vitro. Therefore, this in vitro system is a powerful tool to study the role of mechanical signaling in NCCs and its interaction with chemical signals, which will help researchers better understand the molecular and genetic mechanisms of neural crest development and diseases.

Hidrogéis , Crista Neural , Diferenciação Celular , Movimento Celular , Microscopia de Força Atômica , Células-Tronco Multipotentes
J Cardiovasc Dev Dis ; 8(8)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34436231


The neural crest (NC) is a multipotent and temporarily migratory cell population stemming from the dorsal neural tube during vertebrate embryogenesis. Cardiac neural crest cells (NCCs), a specified subpopulation of the NC, are vital for normal cardiovascular development, as they significantly contribute to the pharyngeal arch arteries, the developing cardiac outflow tract (OFT), cardiac valves, and interventricular septum. Various signaling pathways are shown to orchestrate the proper migration, compaction, and differentiation of cardiac NCCs during cardiovascular development. Any loss or dysregulation of signaling pathways in cardiac NCCs can lead to abnormal cardiovascular development during embryogenesis, resulting in abnormalities categorized as congenital heart defects (CHDs). This review focuses on the contributions of cardiac NCCs to cardiovascular formation, discusses cardiac defects caused by a disruption of various regulatory factors, and summarizes the role of multiple signaling pathways during embryonic development. A better understanding of the cardiac NC and its vast regulatory network will provide a deeper insight into the mechanisms of the associated abnormalities, leading to potential therapeutic advancements.

Front Cell Dev Biol ; 9: 706623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307386


Neural crest (NC) cells are a migratory stem cell population in vertebrate embryogenesis that can give rise to multiple cell types, including osteoblasts, chondrocytes, smooth muscle cells, neurons, glia, and melanocytes, greatly contributing to the development of different tissues and organs. Defects in NC development are implicated in many human diseases, such as numerous syndromes, craniofacial aberration and congenital heart defects. Research on NC development has gained intense interest and made significant progress. Recent studies showed that the Hippo-Yap pathway, a conserved fundamental pathway with key roles in regulation of cell proliferation, survival, and differentiation, is indispensable for normal NC development. However, the roles and mechanisms of the Hippo-Yap pathway in NC development remain largely unknown. In this review, we summarize the key functions of the Hippo-Yap pathway indicated in NC induction, migration, proliferation, survival, and differentiation, as well as the diseases caused by its dysfunction in NC cells. We also discuss emerging current and future studies in the investigation of the Hippo-Yap pathway in NC development.