scholarly journals Molecular Network Analysis Suggests Aberrant CREB-Mediated Gene Regulation in the Alzheimer Disease Hippocampus

2009 ◽  
Vol 27 (5) ◽  
pp. 239-252 ◽  
Author(s):  
Jun-ichi Satoh ◽  
Hiroko Tabunoki ◽  
Kunimasa Arima
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Alzheimer Disease ◽  
Molecular Interactions ◽  
Hippocampal Neurons ◽  
Early Stage ◽  
Molecular Network ◽  
System Level ◽  
Molecular Networks ◽  
Granulovacuolar Degeneration

The pathogenesis of Alzheimer disease (AD) involves the complex interaction between genetic and environmental factors affecting multiple cellular pathways. Recent advances in systems biology provide a system-level understanding of AD by elucidating the genome-wide molecular interactions. By using KeyMolnet, a bioinformatics tool for analyzing molecular interactions on the curated knowledgebase, we characterized molecular network of 2,883 all stages of AD-related genes (ADGs) and 559 incipient AD-related genes (IADGs) identified by global gene expression profiling of the hippocampal CA1 region of AD brains in terms of significant clinical and pathological correlations (Blalock et al., Proc Natl Acad Sci USA 101: 2173-2178, 2004). By the common upstream search, KeyMolnet identified cAMP-response element-binding protein (CREB) as the principal transcription factor exhibiting the most significant relevance to molecular networks of both ADGs and IADGs. The CREB-regulated transcriptional network included upregulated and downregulated sets of ADGs and IADGs, suggesting an involvement of generalized deregulation of the CREB signaling pathway in the pathophysiology of AD, beginning at the early stage of the disease. To verify thein silicoobservationsin vivo, we conducted immunohistochemical studies of 11 AD and 13 age-matched control brains by using anti-phoshorylated CREB (pCREB) antibody. An abnormal accumulation of pCREB imunoreactivity was identified in granules of granulovacuolar degeneration (GVD) in the hippocampal neurons of AD brains. These observations suggest that aberrant CREB-mediated gene regulation serves as a molecular biomarker of AD-related pathological processes, and support the hypothesis that sequestration of pCREB in GVD granules is in part responsible for deregulation of CREB-mediated gene expression in AD hippocampus.

scholarly journals Exploring the Genetic Basis of Human Population Differences in DNA Methylation and their Causal Impact on Immune Gene Regulation

2018 ◽  
Author(s):  
Lucas T. Husquin ◽  
Maxime Rotival ◽  
Maud Fagny ◽  
Hélène Quach ◽  
Nora Zidane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Gene Regulation ◽  
Complex Traits ◽  
Active Role ◽  
System Level ◽  
Immune Gene ◽  
Population Differences ◽  
Mediation Effects ◽  
Causal Impact

AbstractDNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, its genetic determinants, and their respective causal impact on immune gene regulation remain elusive. We report extensive population differences in DNA methylation between individuals of African and European descent — detected in primary monocytes that were used as a model of a major innate immunity cell type. Most of these differences (~70%) were driven by DNA sequence variants nearby CpG sites (meQTLs), which account for ~60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variation in DNA methylation is associated with varying gene expression levels following mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.

scholarly journals Gene expression profiles of thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome reveal novel molecular mechanism

2009 ◽  
Vol 16 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
Yu-fang Bi ◽  
Rui-xin Liu ◽  
Lei Ye ◽  
Hai Fang ◽  
Xiao-ying Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neuroendocrine Tumors ◽  
Expression Profiles ◽  
Gene Expression Pattern ◽  
Gene Expression Profiles ◽  
Notch Signaling Pathway ◽  
System Level ◽  
Molecular Networks ◽  
Ectopic Acth Syndrome ◽  
Ectopic Acth

Although there has been increased knowledge about the molecular biology of neuroendocrine tumors (NETs), little is known about thymic carcinoids and even less about those with excessive hormone disorders, such as ectopic ACTH syndrome. This study was designed to gain insights into the molecular networks underlying the tumorigenesis of thymic carcinoids with ACTH secretion. By an approach integrating cDNA microarray and methods of computational biology, we compare gene expression profile between ACTH-producing thymic carcinoids and the normal thymus. In total, there are 63 biological categories increased and 108 decreased in thymic carcinoids. Cell proliferation was stimulated, which may explain the relatively uncontrolled cell growth of the tumor. Dysregulation of the Notch-signaling pathway was likely to be underlying the neuroendocrine features of this type of tumors. Moreover, inhibition of immunity and increased neuropeptide signaling molecules (POMC and its sorting molecule CPE) made the clinical manifestation reasonable and thus validated the array data. In conclusion, thymic carcinoids have a distinct gene expression pattern from the normal thymus, and they are characterized by deregulations of a series of biofunctions, which may be involved in the development of NETs. Hence, this study has provided not only a detailed comprehension of the molecular pathogenesis of thymic carcinoids with ectopic ACTH syndrome, but also a road map to approach thymic NETs at the system level.

scholarly journals Anomalous Gene Expression in Alzheimer Disease: Cause or Effect

1991 ◽  
Vol 18 (S3) ◽  
pp. 414-418 ◽  
Author(s):  
D.R.C. McLachlan ◽  
W.J. Lukiw ◽  
C. Mizzen ◽  
M.E. Percy ◽  
M.J. Somerville ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Alzheimer Disease ◽  
Light Chain ◽  
Pool Size ◽  
Chromatin Conformation

ABSTRACT:Altered chromatin conformation and increased amounts of aluminum have been observed in the brains of patients with Alzheimer disease. These factors have been shown to affect gene regulation. In this report, we describe how these changes may selectively alter the pool size of the human light chain neurofilament gene and play a fundamental role in the expression of this disease.

An Integrated Feature Selection Algorithm for Cancer Classification using Gene Expression Data

2019 ◽  
Vol 21 (9) ◽  
pp. 631-645 ◽  
Author(s):  
Saeed Ahmed ◽  
Muhammad Kabir ◽  
Zakir Ali ◽  
Muhammad Arif ◽  
Farman Ali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Feature Selection ◽  
Gene Expression Data ◽  
Classification Accuracy ◽  
Early Stage ◽  
Small Sample Size ◽  
Feature Selection Method ◽  
Small Sample ◽  
Expression Data ◽  
Base Function

Aim and Objective: Cancer is a dangerous disease worldwide, caused by somatic mutations in the genome. Diagnosis of this deadly disease at an early stage is exceptionally new clinical application of microarray data. In DNA microarray technology, gene expression data have a high dimension with small sample size. Therefore, the development of efficient and robust feature selection methods is indispensable that identify a small set of genes to achieve better classification performance. Materials and Methods: In this study, we developed a hybrid feature selection method that integrates correlation-based feature selection (CFS) and Multi-Objective Evolutionary Algorithm (MOEA) approaches which select the highly informative genes. The hybrid model with Redial base function neural network (RBFNN) classifier has been evaluated on 11 benchmark gene expression datasets by employing a 10-fold cross-validation test. Results: The experimental results are compared with seven conventional-based feature selection and other methods in the literature, which shows that our approach owned the obvious merits in the aspect of classification accuracy ratio and some genes selected by extensive comparing with other methods. Conclusion: Our proposed CFS-MOEA algorithm attained up to 100% classification accuracy for six out of eleven datasets with a minimal sized predictive gene subset.

scholarly journals Inhibitory effect of sodium butyrate on colorectal cancer cells and construction of the related molecular network

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Xi ◽  
Zhuang Jing ◽  
Wu Wei ◽  
Zhang Chun ◽  
Qi Quan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Sodium Butyrate ◽  
Molecular Network ◽  
Differentially Expressed ◽  
Cell Counting ◽  
Molecular Networks ◽  
Ppi Network ◽  
Invasion And Metastasis ◽  
Cerna Network ◽  
Proliferation Ability

Abstract Background Sodium butyrate (NaB) is produced through the fermentation of dietary fiber that is not absorbed and digested by the small intestine. Purpose Here, we aimed to investigate the effects of NaB on the proliferation, invasion, and metastasis of CRC cells and their potential underlying molecular mechanism(s). Methods The cell counting kit-8 (CCK-8) assay and EdU assay were used to detect cell proliferation ability, flow cytometry was used to investigate the induction of apoptosis and cell cycle progression, and the scratch-wound healing and transwell assays were used to evaluate cell migration and invasion, respectively. The human CRC genome information for tissues and CRC cells treated with NaB obtained from the NCBI GEO database was reannotated and used for differential RNA analysis. Functional and pathway enrichment analyses were performed for differentially expressed lncRNAs and mRNAs. A protein-protein interaction (PPI) network for the hub genes was constructed using the Cytoscape software. Targeted miRNAs were predicted based on the lnCeDB database, and a ceRNA network was constructed using the Cytoscape software. The Kaplan-Meier method was used to analyze patient prognosis using the clinical information and exon-seq data for CRC obtained from the Broad Institute’s GDAC Firehose platform. Results NaB decreased the proliferation ability of CRC cells in a dose- and time-dependent manner. The number of apoptotic CRC cells increased with the increase in NaB concentrations, and NaB induced a G1 phase block in CRC cells. Moreover, NaB suppressed the migratory and invasive capabilities of CRC cells. There were 666 differentially expressed mRNAs and 30 differentially expressed lncRNAs involved in the CRC inhibition by NaB. The PPI network and ceRNA network were constructed based on the differentially expressed mRNAs and lncRNAs. Three differentially expressed mRNAs, including HMGA2, LOXL2, and ST7, were significantly correlated with the prognosis of CRC. Conclusion NaB induces the apoptosis and inhibition of CRC cell proliferation, invasion, and metastasis by modulating complex molecular networks. RNA prediction and molecular network construction need to be the focus of further research in this direction.

scholarly journals AAV-Mediated CRISPRi and RNAi Based Gene Silencing in Mouse Hippocampal Neurons

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 324
Author(s):  
Matthias Deutsch ◽  
Anne Günther ◽  
Rodrigo Lerchundi ◽  
Christine R. Rose ◽  
Sabine Balfanz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Initiation ◽  
Hippocampal Neurons ◽  
De Novo ◽  
Protein Biosynthesis ◽  
Physiological Role ◽  
High Specificity ◽  
Hcn Channels ◽  
Proliferating Cells ◽  
Neuronal Tissues

Uncovering the physiological role of individual proteins that are part of the intricate process of cellular signaling is often a complex and challenging task. A straightforward strategy of studying a protein’s function is by manipulating the expression rate of its gene. In recent years, the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9-based technology was established as a powerful gene-editing tool for generating sequence specific changes in proliferating cells. However, obtaining homogeneous populations of transgenic post-mitotic neurons by CRISPR/Cas9 turned out to be challenging. These constraints can be partially overcome by CRISPR interference (CRISPRi), which mediates the inhibition of gene expression by competing with the transcription machinery for promoter binding and, thus, transcription initiation. Notably, CRISPR/Cas is only one of several described approaches for the manipulation of gene expression. Here, we targeted neurons with recombinant Adeno-associated viruses to induce either CRISPRi or RNA interference (RNAi), a well-established method for impairing de novo protein biosynthesis by using cellular regulatory mechanisms that induce the degradation of pre-existing mRNA. We specifically targeted hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, which are widely expressed in neuronal tissues and play essential physiological roles in maintaining biophysical characteristics in neurons. Both of the strategies reduced the expression levels of three HCN isoforms (HCN1, 2, and 4) with high specificity. Furthermore, detailed analysis revealed that the knock-down of just a single HCN isoform (HCN4) in hippocampal neurons did not affect basic electrical parameters of transduced neurons, whereas substantial changes emerged in HCN-current specific properties.

scholarly journals Base-Pair Opening Dynamics Study of Fluoride Riboswitch in the Bacillus cereus CrcB Gene

2021 ◽  
Vol 22 (6) ◽  
pp. 3234
Author(s):  
Juhyun Lee ◽  
Si-Eun Sung ◽  
Janghyun Lee ◽  
Jin Young Kang ◽  
Joon-Hwa Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Nmr Spectroscopy ◽  
Bacillus Cereus ◽  
Base Pair ◽  
Noncoding Rna ◽  
Hydrogen Exchange ◽  
Magnesium Ion ◽  
Fluoride Ion ◽  
Base Pair Opening

Riboswitches are segments of noncoding RNA that bind with metabolites, resulting in a change in gene expression. To understand the molecular mechanism of gene regulation in a fluoride riboswitch, a base-pair opening dynamics study was performed with and without ligands using the Bacillus cereus fluoride riboswitch. We demonstrate that the structural stability of the fluoride riboswitch is caused by two steps depending on ligands. Upon binding of a magnesium ion, significant changes in a conformation of the riboswitch occur, resulting in the greatest increase in their stability and changes in dynamics by a fluoride ion. Examining hydrogen exchange dynamics through NMR spectroscopy, we reveal that the stabilization of the U45·A37 base-pair due to the binding of the fluoride ion, by changing the dynamics while maintaining the structure, results in transcription regulation. Our results demonstrate that the opening dynamics and stabilities of a fluoride riboswitch in different ion states are essential for the genetic switching mechanism.

scholarly journals Competing Endogenous RNAs in Cervical Carcinogenesis: A New Layer of Complexity

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 991
Author(s):  
Fernanda Costa Brandão Berti ◽  
Sara Cristina Lobo-Alves ◽  
Camila de Freitas Oliveira-Toré ◽  
Amanda Salviano-Silva ◽  
Karen Brajão de Oliveira ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fine Tuning ◽  
Molecular Networks ◽  
Cervical Carcinogenesis ◽  
Molecular Changes ◽  
Cellular Processes ◽  
Target Mrnas ◽  
Competing Endogenous Rnas ◽  
Cervical Cells ◽  
Post Transcriptional Regulation

MicroRNAs (miRNAs) regulate gene expression by binding to complementary sequences within target mRNAs. Apart from working ‘solo’, miRNAs may interact in important molecular networks such as competing endogenous RNA (ceRNA) axes. By competing for a limited pool of miRNAs, transcripts such as long noncoding RNAs (lncRNAs) and mRNAs can regulate each other, fine-tuning gene expression. Several ceRNA networks led by different lncRNAs—described here as lncRNA-mediated ceRNAs—seem to play essential roles in cervical cancer (CC). By conducting an extensive search, we summarized networks involved in CC, highlighting the major impacts of such dynamic molecular changes over multiple cellular processes. Through the sponging of distinct miRNAs, some lncRNAs as HOTAIR, MALAT1, NEAT1, OIP5-AS1, and XIST trigger crucial molecular changes, ultimately increasing cell proliferation, migration, invasion, and inhibiting apoptosis. Likewise, several lncRNAs seem to be a sponge for important tumor-suppressive miRNAs (as miR-140-5p, miR-143-3p, miR-148a-3p, and miR-206), impairing such molecules from exerting a negative post-transcriptional regulation over target mRNAs. Curiously, some of the involved mRNAs code for important proteins such as PTEN, ROCK1, and MAPK1, known to modulate cell growth, proliferation, apoptosis, and adhesion in CC. Overall, we highlight important lncRNA-mediated functional interactions occurring in cervical cells and their closely related impact on cervical carcinogenesis.

scholarly journals CFTR Cooperative Cis-Regulatory Elements in Intestinal Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2599
Author(s):  
Mégane Collobert ◽  
Ozvan Bocher ◽  
Anaïs Le Nabec ◽  
Emmanuelle Génin ◽  
Claude Férec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Gene Regulation ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Cftr Gene ◽  
Intestinal Cells ◽  
Cooperative Effects ◽  
Cis Acting ◽  
Study Techniques

About 8% of the human genome is covered with candidate cis-regulatory elements (cCREs). Disruptions of CREs, described as “cis-ruptions” have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator (CFTR) regulatory elements were identified, but the regulatory mechanisms of the CFTR gene have yet to be fully elucidated. The aim of this work is to improve our knowledge of the CFTR gene regulation, and to identity factors that could impact the CFTR gene expression, and potentially account for the variability of the clinical presentation of cystic fibrosis as well as CFTR-related disorders. Here, we apply the robust GWAS3D score to determine which of the CFTR introns could be involved in gene regulation. This approach highlights four particular CFTR introns of interest. Using reporter gene constructs in intestinal cells, we show that two new introns display strong cooperative effects in intestinal cells. Chromatin immunoprecipitation analyses further demonstrate fixation of transcription factors network. These results provide new insights into our understanding of the CFTR gene regulation and allow us to suggest a 3D CFTR locus structure in intestinal cells. A better understand of regulation mechanisms of the CFTR gene could elucidate cases of patients where the phenotype is not yet explained by the genotype. This would thus help in better diagnosis and therefore better management. These cis-acting regions may be a therapeutic challenge that could lead to the development of specific molecules capable of modulating gene expression in the future.

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