scholarly journals Identifying roles for peptidergic signaling in mice

2019 ◽  
Vol 116 (40) ◽  
pp. 20169-20179 ◽  
Author(s):  
Kathryn G. Powers ◽  
Xin-Ming Ma ◽  
Betty A. Eipper ◽  
Richard E. Mains
Keyword(s):  
Gene Expression ◽  
Serum Levels ◽  
Conditional Knockout ◽  
Sequencing Analysis ◽  
Therapeutic Approaches ◽  
Cytoskeletal Organization ◽  
Cell Type Specific ◽  
Screening Platform ◽  
Single Enzyme ◽  
Endocytic Pathways

Despite accumulating evidence demonstrating the essential roles played by neuropeptides, it has proven challenging to use this information to develop therapeutic strategies. Peptidergic signaling can involve juxtacrine, paracrine, endocrine, and neuronal signaling, making it difficult to define physiologically important pathways. One of the final steps in the biosynthesis of many neuropeptides requires a single enzyme, peptidylglycine α-amidating monooxygenase (PAM), and lack of amidation renders most of these peptides biologically inert. PAM, an ancient integral membrane enzyme that traverses the biosynthetic and endocytic pathways, also affects cytoskeletal organization and gene expression. While mice, zebrafish, and flies lacking Pam (PamKO/KO) are not viable, we reasoned that cell type-specific elimination of Pam expression would generate mice that could be screened for physiologically important and tissue-specific deficits. Conditional PamcKO/cKO mice, with loxP sites flanking the 2 exons deleted in the global PamKO/KO mouse, were indistinguishable from wild-type mice. Eliminating Pam expression in excitatory forebrain neurons reduced anxiety-like behavior, increased locomotor responsiveness to cocaine, and improved thermoregulation in the cold. A number of amidated peptides play essential roles in each of these behaviors. Although atrial natriuretic peptide (ANP) is not amidated, Pam expression in the atrium exceeds levels in any other tissue. Eliminating Pam expression in cardiomyocytes increased anxiety-like behavior and improved thermoregulation. Atrial and serum levels of ANP fell sharply in PAM myosin heavy chain 6 conditional knockout mice, and RNA sequencing analysis identified changes in gene expression in pathways related to cardiac function. Use of this screening platform should facilitate the development of therapeutic approaches targeted to peptidergic pathways.

scholarly journals Identifying Novel Roles for Peptidergic Signaling in Mice

2019 ◽  
Author(s):  
Kathryn G. Powers ◽  
Xin-Ming Ma ◽  
Betty A. Eipper ◽  
Richard E. Mains
Keyword(s):  
Gene Expression ◽  
Pain Perception ◽  
Serum Levels ◽  
Tissue Specific ◽  
New Therapeutic Approaches ◽  
Cell Type Specific ◽  
Salt And Water Balance ◽  
Screening Platform ◽  
The Many

ABSTRACTDespite accumulating evidence demonstrating the essential roles played by neuropeptides, it has proven challenging to use this information to develop therapeutic strategies. Peptidergic signaling can involve juxtacrine, paracrine, endocrine and neuronal signaling, making it difficult to define physiologically important pathways. One of the final steps in the biosynthesis of many neuropeptides requires a single enzyme, peptidylglycine α-amidating monooxygenase (PAM), and lack of amidation renders most of these peptides biologically inert. PAM, an ancient integral membrane enzyme that traverses the biosynthetic and endocytic pathways, also affects cytoskeletal organization and gene expression. While mice, zebrafish and flies lackingPam(PamKO/KO) are not viable, we reasoned that cell-type specific elimination ofPamexpression would generate mice that could be screened for physiologically important and tissue-specific deficits.PamcKO/cKOmice, with loxP sites flanking the 2 exons deleted in the globalPamKO/KOmouse, were indistinguishable from wildtype mice. EliminatingPamexpression in excitatory forebrain neurons reduced anxiety-like behavior, increased locomotor responsiveness to cocaine and improved thermoregulation in the cold. A number of amidated peptides play essential roles in each of these behaviors. Although atrial natriuretic peptide (ANP) is not amidated,Pamexpression in the atrium exceeds levels in any other tissue. EliminatingPamexpression in cardiomyocytes increased anxiety-like behavior and improved thermoregulation. Atrial and serum levels of ANP fell sharplyPamMyh6-cKO/cKOin mice and RNASeq analysis identified changes in gene expression in pathways related to cardiac function. Use of this screening platform should facilitate the development of new therapeutic approaches targeted to peptidergic pathways.SIGNIFICANCEPeptidergic signaling, which plays key roles in the many pathways that control thermoregulation, salt and water balance, metabolism, anxiety, pain perception and sexual reproduction, is essential for the maintenance of homeostasis. Despite the fact that peptides generally signal through G protein coupled receptors, it has proven difficult to use knowledge about peptide synthesis, storage and secretion to develop effective therapeutics. Our goal was to develop anin vivobioassay system that would reveal physiologically meaningful deficits associated with disturbed peptidergic signaling. We did so by developing a system in which an enzyme essential for the production of many bioactive peptides could be eliminated in a tissue-specific manner.

A New Approach for Predicting the Value of Gene Expression: Two-way Collaborative Filtering

2019 ◽  
Vol 14 (6) ◽  
pp. 480-490 ◽  
Author(s):  
Tuncay Bayrak ◽  
Hasan Oğul
Keyword(s):  
Gene Expression ◽  
Regression Model ◽  
Collaborative Filtering ◽  
High Throughput Sequencing ◽  
Mean Squared Error ◽  
Experimental Studies ◽  
Kernel Functions ◽  
Feature Representation ◽  
Sequencing Analysis ◽  
Computational Systems Biology

Background: Predicting the value of gene expression in a given condition is a challenging topic in computational systems biology. Only a limited number of studies in this area have provided solutions to predict the expression in a particular pattern, whether or not it can be done effectively. However, the value of expression for the measurement is usually needed for further meta-data analysis. Methods: Because the problem is considered as a regression task where a feature representation of the gene under consideration is fed into a trained model to predict a continuous variable that refers to its exact expression level, we introduced a novel feature representation scheme to support work on such a task based on two-way collaborative filtering. At this point, our main argument is that the expressions of other genes in the current condition are as important as the expression of the current gene in other conditions. For regression analysis, linear regression and a recently popularized method, called Relevance Vector Machine (RVM), are used. Pearson and Spearman correlation coefficients and Root Mean Squared Error are used for evaluation. The effects of regression model type, RVM kernel functions, and parameters have been analysed in our study in a gene expression profiling data comprising a set of prostate cancer samples. Results: According to the findings of this study, in addition to promising results from the experimental studies, integrating data from another disease type, such as colon cancer in our case, can significantly improve the prediction performance of the regression model. Conclusion: The results also showed that the performed new feature representation approach and RVM regression model are promising for many machine learning problems in microarray and high throughput sequencing analysis.

scholarly journals Methyltransferases in the Pathogenesis of Keratinocyte Cancers

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3402
Author(s):  
Eun Kyung Ko ◽  
Brian C. Capell
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Basal Cell ◽  
Histone Methylation ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Therapeutic Approaches ◽  
Novel Therapeutic

Recent evidence suggests that the disruption of gene expression by alterations in DNA, RNA, and histone methylation may be critical contributors to the pathogenesis of keratinocyte cancers (KCs), made up of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which collectively outnumber all other human cancers combined. While it is clear that methylation modifiers are frequently dysregulated in KCs, the underlying molecular and mechanistic changes are only beginning to be understood. Intriguingly, it has recently emerged that there is extensive cross-talk amongst these distinct methylation processes. Here, we summarize and synthesize the latest findings in this space and highlight how these discoveries may uncover novel therapeutic approaches for these ubiquitous cancers.

scholarly journals Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiao Li ◽  
Jakob Seidlitz ◽  
John Suckling ◽  
Feiyang Fan ◽  
Gong-Jun Ji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Structural Changes ◽  
Brain Regions ◽  
Cell Type ◽  
Major Depressive ◽  
Structural Differences ◽  
Neuroimaging Data ◽  
Cell Type Specific

AbstractMajor depressive disorder (MDD) has been shown to be associated with structural abnormalities in a variety of spatially diverse brain regions. However, the correlation between brain structural changes in MDD and gene expression is unclear. Here, we examine the link between brain-wide gene expression and morphometric changes in individuals with MDD, using neuroimaging data from two independent cohorts and a publicly available transcriptomic dataset. Morphometric similarity network (MSN) analysis shows replicable cortical structural differences in individuals with MDD compared to control subjects. Using human brain gene expression data, we observe that the expression of MDD-associated genes spatially correlates with MSN differences. Analysis of cell type-specific signature genes suggests that microglia and neuronal specific transcriptional changes account for most of the observed correlation with MDD-specific MSN differences. Collectively, our findings link molecular and structural changes relevant for MDD.

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