Integration of probabilistic regulatory networks into constraint-based models of metabolism with applications to Alzheimer’s disease

Background: Numerous studies have shown a significant association between type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD), two pathologies affecting millions of people worldwide. Chronic inflammation and oxidative stress are two conditions common to these diseases also affecting the activity of the serpin alpha-1-antichymotrypsin (ACT), but a possible common role for this serpin in T2D and AD remains unclear. Objective: To explore the possible regulatory networks linking ACT to T2D and AD. Materials and Methods: A bibliographic search was carried out in PubMed, Med-line, Open-i, ScienceDirect, Scopus and SpringerLink for data indicating or suggesting association among T2D, AD, and ACT. Searched terms like “alpha-1-antichymotrypsin”, “type 2 diabetes”, “Alzheimer's disease”, “oxidative stress”, “pro-inflammatory mediators” among others were used. Moreover, common therapeutic strategies between T2D and AD as well as the use of ACT as a therapeutic target for both diseases were included. Results: ACT has been linked with development and maintenance of T2D and AD and studies suggest their participation through activation of inflammatory pathways and oxidative stress, mechanisms also associated with both diseases. Likewise, evidences indicate that diverse therapeutic approaches are common to both diseases. Conclusion: Inflammatory and oxidative stresses constitute a crossroad for T2D and AD where ACT could play an important role. In-depth research on ACT involvement in these two dysfunctions could generate new therapeutic strategies for T2D and AD.

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Integrative multi-omics analyses identify cell-type disease genes and regulatory networks across schizophrenia and Alzheimer’s disease

10.1101/2020.06.11.147314 ◽

2020 ◽

Author(s):

Mufang Ying ◽

Peter Rehani ◽

Panagiotis Roussos ◽

Daifeng Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Regulatory Elements ◽

Disease Genes ◽

Omics Data ◽

Cell Type ◽

Cellular Resolution ◽

Gene Regulatory

AbstractStrong phenotype-genotype associations have been reported across brain diseases. However, understanding underlying gene regulatory mechanisms remains challenging, especially at the cellular level. To address this, we integrated the multi-omics data at the cellular resolution of the human brain: cell-type chromatin interactions, epigenomics and single cell transcriptomics, and predicted cell-type gene regulatory networks linking transcription factors, distal regulatory elements and target genes (e.g., excitatory and inhibitory neurons, microglia, oligodendrocyte). Using these cell-type networks and disease risk variants, we further identified the cell-type disease genes and regulatory networks for schizophrenia and Alzheimer’s disease. The celltype regulatory elements (e.g., enhancers) in the networks were also found to be potential pleiotropic regulatory loci for a variety of diseases. Further enrichment analyses including gene ontology and KEGG pathways revealed potential novel cross-disease and disease-specific molecular functions, advancing knowledge on the interplays among genetic, transcriptional and epigenetic risks at the cellular resolution between neurodegenerative and neuropsychiatric diseases. Finally, we summarized our computational analyses as a general-purpose pipeline for predicting gene regulatory networks via multi-omics data.

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Genetics of the human microglia regulome refines Alzheimer's disease risk loci

10.1101/2021.10.17.21264910 ◽

2021 ◽

Author(s):

Roman Kosoy ◽

John Fullard ◽

Biao Zeng ◽

Jaroslav Bendl ◽

Pengfei Dong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Regulatory Networks ◽

Disease Risk ◽

Single Gene ◽

Critical Role ◽

Chromatin Accessibility ◽

Human Microglia ◽

Mapping Analysis ◽

Regulatory Landscape

Microglia are brain resident myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer's Disease (AD). Yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to disease is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically-driven variation and cell-specific enhancer-promoter interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 novel genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides novel insights into the etiology of neurodegenerative disease.

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Ensemble graphs to reveal post-transcriptional regulatory networks in Alzheimer's disease

2017 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) ◽

10.1109/bibm.2017.8217667 ◽

2017 ◽

Author(s):

Ruben Armananzas

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Regulatory Networks ◽

Transcriptional Regulatory Networks ◽

Transcriptional Regulatory

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O3-03-01: MECHANISTIC AND DIRECTIONAL TRANSCRIPTIONAL REGULATORY NETWORKS IN ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.2782 ◽

2006 ◽

Vol 14 (7S_Part_19) ◽

pp. P1014-P1015

Author(s):

Cory C. Funk ◽

Matthew A. Richards ◽

Paul Shannon ◽

Rory Donovan-Maiye ◽

Noa Rappaport ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Regulatory Networks ◽

Transcriptional Regulatory Networks ◽

Transcriptional Regulatory

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The three-dimensional landscape of chromatin accessibility in Alzheimer’s disease

10.1101/2021.01.11.426303 ◽

2021 ◽

Author(s):

Jaroslav Bendl ◽

Mads E. Hauberg ◽

Kiran Girdhar ◽

Eunju Im ◽

James M. Vicari ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Regulatory Networks ◽

3D Structure ◽

Three Dimensional ◽

Superior Temporal Gyrus ◽

Brain Regions ◽

Chromatin Accessibility ◽

Regulatory Sequences ◽

3D Genome

AbstractMuch is still unknown about the neurobiology of Alzheimer’s disease (AD). To better understand AD, we generated 636 ATAC-seq libraries from cases and controls to construct detailed genomewide chromatin accessibility maps of neurons and non-neurons from two AD-affected brain regions, the entorhinal cortex and superior temporal gyrus. By analyzing a total of 19.6 billion read pairs, we expanded the known repertoire of regulatory sequences in the human brain. Multi-omic data integration associated global patterns of chromatin accessibility with gene expression and identified cell-specific enhancer-promoter interactions. Using inter-individual variation in chromatin accessibility, we define cis-regulatory domains capturing the 3D structure of the genome. Multifaceted analyses uncovered disease associated perturbations impacting chromatin accessibility, transcription factor regulatory networks and the 3D genome, and implicated transcriptional dysregulation in AD. Overall, we applied a systematic approach to understand the role of the 3D genome in AD and to illuminate novel disease biology that can advance diagnosis and therapy.

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Construction of Long Noncoding RNA-Associated ceRNA Networks Reveals Potential Biomarkers in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210068 ◽

2021 ◽

pp. 1-15

Author(s):

Guan-yong Ou ◽

Wen-wen Lin ◽

Wei-jiang Zhao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Noncoding Rna ◽

Regulatory Networks ◽

Enrichment Analysis ◽

Brain Regions ◽

Functional Enrichment ◽

Receptor Interaction ◽

Hub Genes ◽

Potential Biomarkers

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that seriously impairs both cognitive and memory functions mainly in the elderly, and its incidence increases with age. Recent studies demonstrated that long noncoding RNAs (lncRNAs) play important roles in AD by acting as competing endogenous RNAs (ceRNAs). Objective: In this study, we aimed to construct lncRNA-associated ceRNA regulatory networks composed of potential biomarkers in AD based on the ceRNA hypothesis. Methods: A total of 20 genes (10 upregulated genes and 10 downregulated genes) were identified as the hub differentially expressed genes (DEGs). The functional enrichment analysis showed that the most significant pathways of DEGs involved include retrograde endocannabinoid signaling, synaptic vesicle circle, and AD. The upregulated hub genes were mainly enriched in the cytokine-cytokine receptor interaction pathway, whereas downregulated hub genes were involved in the neuroactive ligand-receptor interaction pathway. After convergent functional genomic (CFG) ranks and expression level analysis in different brain regions of hub genes, we found that CXCR4, GFAP, and GNG3 were significantly correlated with AD. We further identified crucial miRNAs and lncRNAs of targeted genes to construct lncRNA-associated ceRNA regulatory networks. Results: The results showed that two lncRNAs (NEAT1, MIAT), three miRNAs (hsa-miR-551a, hsa-miR-133b and hsa-miR-206), and two mRNA (CXCR4 and GNG3), which are highly related to AD, were preliminarily identified as potential AD biomarkers. Conclusion: Our study provides new insights for understanding the pathogenic mechanism underlying AD, which may potentially contribute to the ceRNA mechanism in AD.

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