scholarly journals Co-regulatory networks of human serum proteins link genetics to disease

Science ◽  
2018 ◽  
Vol 361 (6404) ◽  
pp. 769-773 ◽  
Author(s):  
Valur Emilsson ◽  
Marjan Ilkov ◽  
John R. Lamb ◽  
Nancy Finkel ◽  
Elias F. Gudmundsson ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Complex Disease ◽  
Serum Proteins ◽  
Extracellular Proteins ◽  
Regulatory Control ◽  
Pairwise Correlation ◽  
Disease States ◽  
Age Related ◽  
Network Modules ◽  
Cis And Trans

Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.

scholarly journals Transcriptional regulation of metabolism in disease: From transcription factors to epigenetics

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5062 ◽  
Author(s):  
Liam J. Hawkins ◽  
Rasha Al-attar ◽  
Kenneth B. Storey
Keyword(s):  
Transcriptional Regulation ◽  
Genomic Sequence ◽  
Regulatory Elements ◽  
Regulatory Pathways ◽  
Transcriptional Dysregulation ◽  
Disease States ◽  
Specific Subset ◽  
Transcriptional Regulatory ◽  
Cis And Trans ◽  
Or Genes

Every cell in an individual has largely the same genomic sequence and yet cells in different tissues can present widely different phenotypes. This variation arises because each cell expresses a specific subset of genomic instructions. Control over which instructions, or genes, are expressed is largely controlled by transcriptional regulatory pathways. Each cell must assimilate a huge amount of environmental input, and thus it is of no surprise that transcription is regulated by many intertwining mechanisms. This large regulatory landscape means there are ample possibilities for problems to arise, which in a medical context means the development of disease states. Metabolism within the cell, and more broadly, affects and is affected by transcriptional regulation. Metabolism can therefore contribute to improper transcriptional programming, or pathogenic metabolism can be the result of transcriptional dysregulation. Here, we discuss the established and emerging mechanisms for controling transcription and how they affect metabolism in the context of pathogenesis. Cis- and trans-regulatory elements, microRNA and epigenetic mechanisms such as DNA and histone methylation, all have input into what genes are transcribed. Each has also been implicated in diseases such as metabolic syndrome, various forms of diabetes, and cancer. In this review, we discuss the current understanding of these areas and highlight some natural models that may inspire future therapeutics.

scholarly journals Identification of drugs for leukaemia differentiation therapy by network pharmacology

2019 ◽  
Author(s):  
Eleni G Christodoulou ◽  
Lin Ming Lee ◽  
Kian Leong Lee ◽  
Tsz Kan Fung ◽  
Eric So ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cellular Reprogramming ◽  
Network Pharmacology ◽  
Differentiation Therapy ◽  
Disease States ◽  
Small Molecule Drugs ◽  
Transcriptional Changes ◽  
Gene Regulatory ◽  
Computational Platform

AbstractAcute leukaemias differ from their normal haematopoietic counterparts in their inability to differentiate. This phenomenon is thought to be the result of aberrant cellular reprogramming involving transcription factors (TFs). Here we leveraged on Mogrify, a network-based algorithm, to identify TFs and their gene regulatory networks that drive differentiation of the acute promyelocytic leukaemia (APL) cell line NB4 in response to ATRA (all-transretinoic acid). We further integrated the detected TF regulatory networks with the Connectivity Map (CMAP) repository and recovered small molecule drugs which induce similar transcriptional changes. Our method outperformed standard approaches, retrieving ATRA as the top hit. Of the other drug hits, dimaprit and mebendazole enhanced ATRA-mediated differentiation in both parental NB4 and ATRA-resistant NB4-MR2 cells. Thus, we provide proof-of-principle of our network-based computational platform for drug discovery and repositioning in leukaemia differentiation therapy, which can be extended to other dysregulated disease states.

scholarly journals Integrated Analysis of lncRNAs, mRNAs, and TFs to Identify Regulatory Networks Underlying MAP Infection in Cattle

2021 ◽  
Vol 12 ◽  
Author(s):  
Maryam Heidari ◽  
Abbas Pakdel ◽  
Mohammad Reza Bakhtiarizadeh ◽  
Fariba Dehghanian
Keyword(s):  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Johne's Disease ◽  
Johne’S Disease ◽  
Functional Enrichment ◽  
Integrated Analysis ◽  
Complex Nature ◽  
Hub Genes ◽  
Cis And Trans

Johne’s disease is a chronic infection of ruminants that burdens dairy herds with a significant economic loss. The pathogenesis of the disease has not been revealed clearly due to its complex nature. In order to achieve deeper biological insights into molecular mechanisms involved in MAP infection resulting in Johne’s disease, a system biology approach was used. As far as is known, this is the first study that considers lncRNAs, TFs, and mRNAs, simultaneously, to construct an integrated gene regulatory network involved in MAP infection. Weighted gene coexpression network analysis (WGCNA) and functional enrichment analysis were conducted to explore coexpression modules from which nonpreserved modules had altered connectivity patterns. After identification of hub and hub-hub genes as well as TFs and lncRNAs in the nonpreserved modules, integrated networks of lncRNA-mRNA-TF were constructed, and cis and trans targets of lncRNAs were identified. Both cis and trans targets of lncRNAs were found in eight nonpreserved modules. Twenty-one of 47 nonpreserved modules showed significant biological processes related to the immune system and MAP infection. Some of the MAP infection’s related pathways in the most important nonpreserved modules comprise “positive regulation of cytokine-mediated signaling pathway,” “negative regulation of leukocyte migration,” “T-cell differentiation,” “neutrophil activation,” and “defense response.” Furthermore, several genes were identified in these modules, including SLC11A1, MAPK8IP1, HMGCR, IFNGR1, CMPK2, CORO1A, IRF1, LDLR, BOLA-DMB, and BOLA-DMA, which are potentially associated with MAP pathogenesis. This study not only enhanced our knowledge of molecular mechanisms behind MAP infection but also highlighted several promising hub and hub-hub genes involved in macrophage-pathogen interaction.

scholarly journals Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Jialiang Yang ◽  
◽  
Tao Huang ◽  
Francesca Petralia ◽  
Quan Long ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Disease ◽  
Principal Component ◽  
Tissue Expression ◽  
Whole Body ◽  
Disease Genes ◽  
Related Gene ◽  
Tissue Specific ◽  
Age Related ◽  
Holistic Understanding

Abstract Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed and some essential tissues (e.g., heart and lung) show much stronger “co-aging” than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases.

scholarly journals Passage of serum-destined proteins through the Golgi apparatus of rat liver. An examination of heavy and light Golgi fractions.

1978 ◽  
Vol 76 (1) ◽  
pp. 87-97 ◽  
Author(s):  
J J Bergeron ◽  
D Borts ◽  
J Cruz
Keyword(s):  
Golgi Apparatus ◽  
Rat Liver ◽  
Gel Electrophoresis ◽  
Intracellular Transport ◽  
Serum Proteins ◽  
Polyacrylamide Gel Electrophoresis ◽  
Secretory Protein ◽  
Pulse Injection ◽  
Cis And Trans ◽  
In Cis

The participation of hepatic Golgi apparatus in the intracellular transport of blood-destined proteins has been analyzed using Golgi fractions enriched in cis and trans components of the Golgi apparatus. SDS-polyacrylamide gel electrophoresis of the liver Golgi fractions showed several proteins corresponding in relative proportions and mobilities with serum proteins. After a pulse injection of labeled leucine, the secretory content of the cis Golgi fraction was labeled earlier than the trans Golgi fraction. Taken together, the results show the participation of the liver Golgi apparatus in the secretion of most of the serum proteins and provide documentation for a sequential progression of secretory protein through the cis and trans components of the Golgi apparatus.

scholarly journals Newborn screening for sickle cell disorders using tandem mass spectrometry: three years’ experience of using a protocol to detect only the disease states

2017 ◽  
Vol 54 (5) ◽  
pp. 601-611 ◽  
Author(s):  
Stuart J Moat ◽  
Derek Rees ◽  
Roanna S George ◽  
Lawrence King ◽  
Alan Dodd ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Newborn Screening ◽  
Sickle Cell ◽  
Tandem Mass ◽  
Wild Type ◽  
Disease States ◽  
Age Related ◽  
Screening Protocol ◽  
Sickle Cell Disorders

Background Tandem mass spectrometry (MS/MS) has recently become an alternative method for the newborn screening of sickle cell disorders (SCD), as it is able to detect haemoglobin (Hb) peptides following digestion of bloodspots with trypsin. Using the SpOtOn Diagnostics Reagent Kit, we previously developed a screening protocol to detect only the disease states of SCD, using action values based on the ratio between the variant Hb peptide to wild-type peptide abundances for the HbS, C, DPunjab, OArab, E and Lepore peptides. Methods Action values using the ratios between the wild type HbA (ßT1-3) peptides and the foetal Hb (γT2) peptide were developed to identify bloodspot samples from premature and transfused infants. An evaluation was undertaken to assess the transferability of the action values onto an additional MS/MS instrument. We report here our experience using this MS/MS protocol. Results During a three-year period, we screened 100,456 babies and identified 10 SCD cases (1 HbS/HPFH, 5 HbS/S and 4 HbS/C) and a case of HbE/ß-thalassaemia that was identified as a by-product. The Hb variant to wild-type peptide ratio action values were transferable to a second MS/MS instrument. Our protocol prevented the identification of an estimated 810 carrier infants. Gestational age-related action values for HbA to HbF peptide ratios were required to minimize the number of samples referred for second-line testing to exclude ß-thalassaemia. Conclusion MS/MS is a robust alternative screening technology for SCD; in addition, it also optimizes the use of equipment and expertise that currently exist in newborn screening laboratories.

scholarly journals Neural Substrates of Self-Regulatory Control in Children and Adults with Tourette Syndrome

2009 ◽  
Vol 54 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Amir Raz ◽  
Hongtu Zhu ◽  
Shan Yu ◽  
Ravi Bansal ◽  
Zhishun Wang ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Self Regulation ◽  
Age Groups ◽  
Cortical Activation ◽  
Regulatory Control ◽  
Tic Disorder ◽  
Compulsive Disorder ◽  
Control Subjects ◽  
Age Related ◽  
Axis I

Objective: To identify the neural substrate of self-regulatory control in children and adults with Tourette syndrome (TS). Method: We used event-related functional magnetic resonance imaging (fMRI) to study the neural correlates of cognitive self-regulation during the Simon task. Forty-two people from The Tic Disorder Specialty Clinic who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for diagnosis with TS (24 children; 18 adults) were compared with 37 control subjects (19 children; 18 adults). Patients with TS were excluded from participation if they had any Axis I psychiatric disorder other than obsessive–compulsive disorder (OCD) or attention-deficit hyperactivity disorder (ADHD) prior to the onset of TS. Control participants were excluded if they reported a history of tic disorder, OCD, ADHD, or if they met diagnostic criteria for any Axis I disorder at the time of interview. Results: We detected greater overall fMRI activation in adults than in children across both diagnostic groups, primarily in frontal and striatal regions. In both groups we also detected an age-related shift away from more general cortical activation toward a more specific reliance on frontostriatal activity, a developmental correlate that was exaggerated in the TS group despite behavioural performances similar to those of control subjects. Moreover, the severity of tics correlated positively with frontal activations across age groups. Conclusion: Frontostriatal circuits support cognitive and behavioural control. These circuits likely contribute both to optimal performance in this self-regulatory task and to the regulation of the severity of tics. Adults with persistent TS likely possess deficient activity in these circuits, attributable to either a failure of prefrontal plasticity or to disturbances in striatal functioning.

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