Common Dysregulated Pathways Research Articles

A Multi-Omics Approach Revealed Common Dysregulated Pathways in Type One and Type Two Endometrial Cancers.

Endometrial cancer (EC) is the most frequent gynecologic cancer in postmenopausal women. Pathogenetic mechanisms that are related to the onset and progression of the disease are largely still unknown. A multi-omics strategy can help identify altered pathways that could be targeted for improving therapeutical approaches. In this study we used a multi-omics approach on four EC cell lines for the identification of common dysregulated pathways in type 1 and 2 ECs. We analyzed proteomics and metabolomics of AN3CA, HEC1A, KLE and ISHIKAWA cell lines by mass spectrometry. The bioinformatic analysis identified 22 common pathways that are in common with both types of EC. In addition, we identified five proteins and 13 metabolites common to both types of EC. Western blotting analysis on 10 patients with type 1 and type 2 EC and 10 endometria samples confirmed the altered abundance of NPEPPS. Our multi-omics analysis identified dysregulated proteins and metabolites involved in EC tumor growth. Further studies are needed to understand the role of these molecules in EC. Our data can shed light on common pathways to better understand the mechanisms involved in the development and growth of EC, especially for the development of new therapies.

Abstract P2059: Poly(rC)-binding Protein-1 (Pcbp1) Is Essential For Heart Development

Rationale: Proper development of the heart relies on a tightly regulated, yet diverse, pattern of gene expression that is governed by transcriptional, post-transcriptional, and translational processes. Congenital heart disease (CHD) is the most common birth defect and a leading cause of morbidity and mortality in children. While the genetic cause of some types of CHD has been identified, the molecular basis for the rest remains elusive. Poly(rC)-binding protein 1 (Pcbp1) is a RNA-binding protein that regulates RNA processing as well as post-transcriptional and translational processes in a variety of biological systems. Hypothesis: Pcbp1 play a critical role in regulating heart development by governing Notch and UPR pathways and mediating proper Aars2 gene splicing. Methods and Results: Germline deletion of Pcbp1 results in lethality before embryonic day (E) 8.5. We generated a cardiac-specific deletion of Pcbp1 by crossing Pcbp1-Flox with cTNT-Cre mice (Pcbp1-cKO cTNT ) and found that Pcbp1-cKO cTNT mice is 50% lethal perinatally. Embryonic hearts of Pcbp1-cKO cTNT mice displayed ventricular non-compaction and abnormal ventricular apex formation. Deep RNA sequencing of Pcbp1-cKO cTNT hearts revealed alteration of gene expression profiles reflective on ventricular maturation delay and dysregulation of Notch and UPR pathways. Interestingly, loss of Pcbp1 in cardiomyocytes disrupts alternative splicing of many important genes including Aars2, a gene associated with congenital mitochondrial cardiomyopathy. Pcbp1 deficiency resulted in creation of an Aars2 exon16-skipping variant, leading to its premature termination. eCLIP-seq showed that Pcbp1 primarily binds to CU-rich motifs at 3’UTR, distal intron and CDS regions of targets, and it interacts with regions of Aars2 transcript near exon 16. Using CRISPR/Cas9 technology, we knocked in loxP sites flanking the exon 16 of Aars2 (Aars2-Flox), and cross the floxed mice with cTNT-Cre mice to generate cardiac-specific exon16 deletion mutant of Aars2 (Aars2-cKO cTNT ). Intriguingly, abnormality in Aars2-cKO cTNT embryonic heart phenocopy aspects of ventricular non-compaction and malformation observed in Pcbp1-cKO cTNT heart. Accordingly, the transcriptome from hearts of Pcbp1-cKO cTNT and Aars2-cKO cTNT display high concordance and similarity and share strikingly common dysregulated pathways. Conclusions: We discover a novel function of Pcbp1 in heart development by regulating Notch and UPR pathways. Additionally, Pcbp1 is indispensable for Aars2 gene splicing, whose deficiency is associated with congenital cardiomyopathy. Our findings suggest modulating Pcbp1 in developing hearts may offer a novel therapeutic intervention for congenital heart failure.

Abstract 658: AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation

Abstract Lineage plasticity contributes to therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon drives neuroendocrine (NE) and squamous cell (LUSC) histologic transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is lower than that of either LUAD or de novo LUSC patients. To date, little is known about the molecular effectors enhancing lineage plasticity and driving histological transdifferentiation due to the paucity of well annotated pre- and post-transdifferentiation clinical samples amenable for molecular analyses. Currently no specific therapies for LUSC or NE transdifferentiation prevention are available for patients at high risk of transformation. We performed multi-omic profiling of transdifferentiating clinical samples, as well as control never-transformed LUAD and de novo LUSC and small cell carcinomas, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Our data suggest that histological transdifferentiation is driven by epigenetic -rather than mutational- events, and indicate that transdifferentiated tumors retain molecular features of their previous LUAD state. Integrative analysis revealed biological pathways dysregulated specifically for distinct histological outcomes, including downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses revealed commonly dysregulated pathways for transdifferentiated tumors, including marked downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in EGFR-mutant patient-derived xenograft transdifferentiation models. These results identify common and histology-specific drivers and dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to constrain lineage plasticity and prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation. Citation Format: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yingqian A. Zhan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Umesh K. Bhanot, Jacklynn Egger, Juan Qiu, Elisa de Stanchina, Natasha Rekhtman, Brian Houck-Loomis, Richard P. Koche, Helena A. Yu, Triparna Sen, Charles M. Rudin. AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 658.

AKT inhibition as a therapeutic strategy to constrain histological transdifferentiation in EGFR-mutant lung adenocarcinoma.

e21166 Background: In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation. Methods: We performed multi-omic profiling of LUAD-to-LUSC and LUAD-to-NE transdifferentiating clinical samples, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Clinical findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Results: Our data supports that histological transdifferentiation from LUAD to LUSC or NE tumors is driven by epigenetic remodeling rather than by mutational events, and indicate that transdifferentiated tumors retain epigenomic features of their previous LUAD state. Integrative epigenomic, transcriptomic and protein analysis revealed divergent biological pathways dysregulated for each histological outcome, such as downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses identified commonly dysregulated pathways in both NE- and LUSC-transdifferentiating tumors, including remarkable downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in different EGFR-mutant patient-derived xenograft transdifferentiation models. Conclusions: These results identify common and divergent dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation.

Central and Peripheral Immune Dysregulation in Posttraumatic Stress Disorder: Convergent Multi-Omics Evidence.

Posttraumatic stress disorder (PTSD) is a chronic and multifactorial disorder with a prevalence ranging between 6–10% in the general population and ~35% in individuals with high lifetime trauma exposure. Growing evidence indicates that the immune system may contribute to the etiology of PTSD, suggesting the inflammatory dysregulation as a hallmark feature of PTSD. However, the potential interplay between the central and peripheral immune system, as well as the biological mechanisms underlying this dysregulation remain poorly understood. The activation of the HPA axis after trauma exposure and the subsequent activation of the inflammatory system mediated by glucocorticoids is the most common mechanism that orchestrates an exacerbated immunological response in PTSD. Recent high-throughput analyses in peripheral and brain tissue from both humans with and animal models of PTSD have found that changes in gene regulation via epigenetic alterations may participate in the impaired inflammatory signaling in PTSD. The goal of this review is to assess the role of the inflammatory system in PTSD across tissue and species, with a particular focus on the genomics, transcriptomics, epigenomics, and proteomics domains. We conducted an integrative multi-omics approach identifying TNF (Tumor Necrosis Factor) signaling, interleukins, chemokines, Toll-like receptors and glucocorticoids among the common dysregulated pathways in both central and peripheral immune systems in PTSD and propose potential novel drug targets for PTSD treatment.

Disease-associated c-MYC downregulation in human disorders of transcriptional regulation.

Cornelia de Lange syndrome (CdLS) is a rare multiorgan developmental disorder caused by pathogenic variants in cohesin genes. It is a genetically and clinically heterogeneous dominant (both autosomal and X-linked) rare disease. Increasing experimental evidence indicates that CdLS is caused by a combination of factors, such as gene expression dysregulation, accumulation of cellular damage and cellular aging, which collectively contribute to the CdLS phenotype. The CdLS phenotype overlaps with a number of related diagnoses such as KBG syndrome and Rubinstein-Taybi syndrome both caused by variants in chromatin-associated factors other than cohesin. The molecular basis underlying these overlapping phenotypes is not clearly defined. Here, we found that cells from individuals with CdLS and CdLS-related diagnoses are characterized by global transcription disturbance and share common dysregulated pathways. Intriguingly, c-MYC (subsequently referred to as MYC) is downregulated in all cell lines and represents a convergent hub lying at the center of dysregulated pathways. Subsequent treatment with estradiol restores MYC expression by modulating cohesin occupancy at its promoter region. In addition, MYC activation leads to modification in expression in hundreds of genes, which in turn reduce the oxidative stress level and genome instability. Together, these results show that MYC plays a pivotal role in the etiopathogenesis of CdLS and CdLS-related diagnoses and represents a potential therapeutic target for these conditions.

Molecular Dysregulation in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders with a strong heritable genetic component. At present, ASD is diagnosed solely by behavioral criteria. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD, where rare mutations and s common variants contribute to its susceptibility. Moreover, studies show rare de novo variants, copy number variation and single nucleotide polymorphisms (SNPs) also impact neurodevelopment signaling. Exploration of rare and common variants involved in common dysregulated pathways can provide new diagnostic and therapeutic strategies for ASD. Contributions of current innovative molecular strategies to understand etiology of ASD will be explored which are focused on whole exome sequencing (WES), whole genome sequencing (WGS), microRNA, long non-coding RNAs and CRISPR/Cas9 models. Some promising areas of pharmacogenomic and endophenotype directed therapies as novel personalized treatment and prevention will be discussed.

Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6‐OHDA model of Parkinson's disease

AimsExperimental and clinical evidences demonstrate that common dysregulated pathways are involved in Parkinson’s disease (PD) and type 2 diabetes. Recently, insulin treatment through intranasal (IN) approach has gained attention in PD, although the underlying mechanism of its potential therapeutic effects is still unclear. In this study, we investigated the effects of insulin treatment in a rat model of PD with emphasis on mitochondrial function indices in striatum.MethodsRats were treated with a daily low dose (4IU/day) of IN insulin, starting 72 h after 6‐OHDA‐induced lesion and continued for 14 days. Motor performance, dopaminergic cell survival, mitochondrial dehydrogenases activity, mitochondrial swelling, mitochondria permeability transition pore (mPTP), mitochondrial membrane potential (Δψm), reactive oxygen species (ROS) formation, and glutathione (GSH) content in mitochondria, mitochondrial adenosine triphosphate (ATP), and the gene expression of PGC‐1α, TFAM, Drp‐1, GFAP, and Iba‐1 were assessed.ResultsIntranasal insulin significantly reduces 6‐OHDA‐induced motor dysfunction and dopaminergic cell death. In parallel, it improves mitochondrial function indices and modulates mitochondria biogenesis and fission as well as activation of astrocytes and microglia.ConclusionConsidering the prominent role of mitochondrial dysfunction in PD pathology, IN insulin as a disease‐modifying therapy for PD should be considered for extensive research.

Dynamics of a Protein Interaction Network Associated to the Aggregation of polyQ-Expanded Ataxin-1.

Background: Several experimental models of polyglutamine (polyQ) diseases have been previously developed that are useful for studying disease progression in the primarily affected central nervous system. However, there is a missing link between cellular and animal models that would indicate the molecular defects occurring in neurons and are responsible for the disease phenotype in vivo. Methods: Here, we used a computational approach to identify dysregulated pathways shared by an in vitro and an in vivo model of ATXN1(Q82) protein aggregation, the mutant protein that causes the neurodegenerative polyQ disease spinocerebellar ataxia type-1 (SCA1). Results: A set of common dysregulated pathways were identified, which were utilized to construct cerebellum-specific protein-protein interaction (PPI) networks at various time-points of protein aggregation. Analysis of a SCA1 network indicated important nodes which regulate its function and might represent potential pharmacological targets. Furthermore, a set of drugs interacting with these nodes and predicted to enter the blood–brain barrier (BBB) was identified. Conclusions: Our study points to molecular mechanisms of SCA1 linked from both cellular and animal models and suggests drugs that could be tested to determine whether they affect the aggregation of pathogenic ATXN1 and SCA1 disease progression.

A myelin-related transcriptomic profile is shared by Pitt-Hopkins syndrome models and human autism spectrum disorder.

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. We analyzed brain transcriptional changes in five mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic form of ASD caused by mutations in TCF4 (transcription factor 4, not TCF7L2 / T-Cell Factor 4). Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. Next, we integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-seq data, and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Importantly, DEGs from syndromic ASD mouse models, and reduced deconvoluted OL numbers, distinguished human idiopathic ASD cases from controls across three postmortem brain datasets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.

Abstract TMP115: Common Transcriptomic and Biomarker Signatures in the Aging Brain and in Mendelian Neurovascular Disease, Cerebral Cavernous Malformation

Background: Cellular senescence is associated with gene expression dysregulation affecting endothelial barrier function as well as angiogenic and inflammatory processes. These pathological changes occur in cerebral cavernous malformations (CCMs), a neurovascular anomaly predisposing patients to hemorrhagic stroke. We hypothesize common transcriptomic and biomarker signatures between the aging brain and CCMs. Method: Brain specific genes dysregulate in Younger (age < 30) and Older (age > 50) human brain parenchyma were identified using the Genotype-Tissue Expression database, and compared with differential transcriptome in microdissected neurovascular units of human CCM lesions. Brain white matter vascular permeability in areas devoid of lesions was measured in non-CCM (23 Younger, 27 Older), Sporadic-CCM (S-CCM) (26 Younger, 37 Older) and Familial-CCM (F-CCM) (41 Younger, 17 Older) using dynamic contrast-enhanced quantitative perfusion MRI. Plasma levels of 6 proteins with reported roles in CCMs were quantified, including VEGF, angiopoietin (ANG 1 & 2), CRP, thrombospondin 2 (THBS 2), and endoglin (ENG). All reported correlations were significant at P< 0.05, FDR corrected. Result: We identified 320 genes (absolute fold change≥1.5) commonly dysregulated in aging brain and CCM, related to inflammation and extracellular matrix organization pathways. Brain permeability was greater in Older non-CCM and S-CCM compared to Younger subjects. Brain permeability was higher in Younger F-CCM harboring germ line CCM mutations, than in both Younger non-CCM (p<0.001) and S-CCM (p<0.05) lacking those mutations. No difference was observed in Younger or Older F-CCM and Older S-CCM or controls. Plasma levels of VEGF, ANG-2 and CRP were greater in both Older non-CCM and S-CCM compared to Younger. No difference was found in Older or Younger F-CCM. No differences were observed in THBS2, ENG and ANG1. Conclusion: There are common transcriptomic, and brain permeability and plasma biomarker signatures in the aging brain and CCM, suggesting common dysregulated pathways. Biomarkers and potential therapies identified in a well characterized Mendelian neurovascular disease may be applicable to mitigate the same mechanistic aberrations in the aging brain.

The impact of spliceosome mutations in MDS.

The impact of spliceosome mutations in MDS.

Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations

AbstractSF3B1, SRSF2, and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34+ cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology.

Fundamental Elements in Autism: From Neurogenesis and Neurite Growth to Synaptic Plasticity.

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders with a high prevalence and impact on society. ASDs are characterized by deficits in both social behavior and cognitive function. There is a strong genetic basis underlying ASDs that is highly heterogeneous; however, multiple studies have highlighted the involvement of key processes, including neurogenesis, neurite growth, synaptogenesis and synaptic plasticity in the pathophysiology of neurodevelopmental disorders. In this review article, we focus on the major genes and signaling pathways implicated in ASD and discuss the cellular, molecular and functional studies that have shed light on common dysregulated pathways using in vitro, in vivo and human evidence.Highlights Autism spectrum disorder (ASD) has a prevalence of 1 in 68 children in the United States.ASDs are highly heterogeneous in their genetic basis.ASDs share common features at the cellular and molecular levels in the brain.Most ASD genes are implicated in neurogenesis, structural maturation, synaptogenesis and function.

MicroRNA in Alzheimer's disease revisited: implications for major neuropathological mechanisms.

Pathology of Alzheimer's disease (AD) goes far beyond neurotoxicity resulting from extracellular deposition of amyloid β (Aβ) plaques. Aberrant cleavage of amyloid precursor protein and accumulation of Aβ in the form of the plaque or neurofibrillary tangles are the known primary culprits of AD pathogenesis and target for various regulatory mechanisms. Hyper-phosphorylation of tau, a major component of neurofibrillary tangles, precipitates its aggregation and prevents its clearance. Lipid particles, apolipoproteins and lipoprotein receptors can act in favor or against Aβ and tau accumulation by altering neural membrane characteristics or dynamics of transport across the blood-brain barrier. Lipids also alter the oxidative/anti-oxidative milieu of the central nervous system (CNS). Irregular cell cycle regulation, mitochondrial stress and apoptosis, which follow both, are also implicated in AD-related neuronal loss. Dysfunction in synaptic transmission and loss of neural plasticity contribute to AD. Neuroinflammation is a final trail for many of the pathologic mechanisms while playing an active role in initiation of AD pathology. Alterations in the expression of microRNAs (miRNAs) in AD and their relevance to AD pathology have long been a focus of interest. Herein we focused on the precise pathomechanisms of AD in which miRNAs were implicated. We performed literature search through PubMed and Scopus using the search term: ('Alzheimer Disease') OR ('Alzheimer's Disease') AND ('microRNAs' OR 'miRNA' OR 'MiR') to reach for relevant articles. We show how a limited number of common dysregulated pathways and abnormal mechanisms are affected by various types of miRNAs in AD brain.

Common dysregulated pathways in obese adipose tissue and atherosclerosis.

BackgroundThe metabolic syndrome is becoming increasingly prevalent in the general population that is at simultaneous risk for both type 2 diabetes and cardiovascular disease. The critical pathogenic mechanisms underlying these diseases are obesity-driven insulin resistance and atherosclerosis, respectively. To obtain a better understanding of molecular mechanisms involved in pathogenesis of the metabolic syndrome as a basis for future treatment strategies, studies considering both inherent risks, namely metabolic and cardiovascular, are needed. Hence, the aim of this study was to identify pathways commonly dysregulated in obese adipose tissue and atherosclerotic plaques.MethodsWe carried out a gene set enrichment analysis utilizing data from two microarray experiments with obese white adipose tissue and atherosclerotic aortae as well as respective controls using a combined insulin resistance-atherosclerosis mouse model.ResultsWe identified 22 dysregulated pathways common to both tissues with p values below 0.05, and selected inflammatory response and oxidative phosphorylation pathways from the Hallmark gene set to conduct a deeper evaluation at the single gene level. This analysis provided evidence of a vast overlap in gene expression alterations in obese adipose tissue and atherosclerosis with Il7r, C3ar1, Tlr1, Rgs1 and Semad4d being the highest ranked genes for the inflammatory response pathway and Maob, Bckdha, Aldh6a1, Echs1 and Cox8a for the oxidative phosphorylation pathway.ConclusionsIn conclusion, this study provides extensive evidence for common pathogenic pathways underlying obesity-driven insulin resistance and atherogenesis which could provide a basis for the development of novel strategies to simultaneously prevent type 2 diabetes and cardiovascular disease in patients with metabolic syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0441-2) contains supplementary material, which is available to authorized users.

Males are from Mars, and females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity

Maternal obesity is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorders, developmental delay, and attention-deficit hyperactivity disorder. The underlying mechanisms remain unclear. We previously identified second-trimester amniotic fluid and term cord blood gene expression patterns suggesting dysregulated brain development in fetuses of obese compared with lean women. We sought to investigate the biological significance of these findings in a mouse model of maternal diet-induced obesity. We evaluated sex-specific differences in fetal growth, brain gene expression signatures, and associated pathways. Female C57BL/6J mice were fed a 60% high-fat diet or 10% fat control diet for 12-14 weeks prior to mating. During pregnancy, obese dams continued on the high-fat diet or transitioned to the control diet. Lean dams stayed on the control diet. On embryonic day 17.5, embryos were weighed and fetal brains were snap frozen. RNA was extracted from male and female forebrains (10 per diet group per sex) and hybridized to whole-genome expression arrays. Significantly differentially expressed genes were identified using a Welch's t test withthe Benjamini-Hochberg correction. Functional analyses were performed using ingenuity pathways analysis and gene set enrichment analysis. Embryos of dams on the high-fat diet were significantly smaller than controls, with males more severely affected than females (P= .01). Maternal obesity and maternal obesity with dietary change in pregnancy resulted in significantly more dysregulated genes in male vs female fetal brains (386 vs 66, P < .001). Maternal obesity with and without dietary change in pregnancy was associated with unique brain gene expression signatures for each sex, with an overlap of only 1 gene. Changing obese dams to a control diet in pregnancy resulted in more differentially expressed genes in the fetal brain than maternal obesity alone. Functional analyses identified common dysregulated pathways in both sexes, but maternal obesity and maternal dietary change affected different aspects of brain development in males compared with females. Maternal obesity is associated with sex-specific differences in fetal size and fetal brain gene expression signatures. Male fetal growth and brain gene expression may be more sensitive toenvironmental influences during pregnancy. Maternal diet during pregnancy has a significant impact on the embryonic brain transcriptome. It is important toconsider both fetal sex and maternal diet when evaluating the effects ofmaternal obesity on fetal neurodevelopment.

8: Males are from Mars, females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity

Maternal obesity (MATOB) is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorder, developmental delay, and ADHD. Underlying mechanisms remain unclear. We previously identified second trimester amniotic fluid gene expression patterns suggesting dysregulated brain development in fetuses of obese (OB) compared to lean (L) women. Here, we characterized fetal brain gene expression signatures and associated pathways in a mouse model of diet-induced obesity. Female (F) C57BL/6J mice were fed a 60% high-fat diet (HFD) or 10% fat control diet (CD) for 10-12 weeks prior to mating. In pregnancy, OB dams continued on the HFD (HFD/HFD), or transitioned to the CD (HFD/CD). L dams stayed on the CD (CD/CD). On embryonic day 17.5, fetal brains were snap frozen. RNA was extracted from male (M) and F brains (10/diet group/sex) and hybridized to whole genome expression arrays. Significantly differentially expressed genes (DEGs) were identified using Welch’s t-test with the Benjamini-Hochberg (BH) correction. False discovery rate of 20% was used as a significance cutoff. Functional analyses were performed using Ingenuity Pathways Analysis™ and Gene Set Enrichment Analysis. MATOB resulted in more dysregulated genes in M (386) vs F (66) fetal brains (p<0.001). MATOB was associated with unique brain gene expression signatures for each sex, with overlap of only one gene (Fig 1). Changing OB dams to a CD in pregnancy induced more DEGs in the fetal brain than MATOB alone. Functional analyses identified common dysregulated pathways in both sexes, but MATOB affected different aspects of brain development in Ms vs Fs (Fig 2). MATOB is associated with sex-specific brain gene expression signatures in M and F embryos. Maternal diet in pregnancy significantly impacts the embryonic brain transcriptome. M brain gene expression may be more sensitive to environmental influences during pregnancy such as MATOB and/or maternal diet. It is important to consider both fetal sex and maternal diet when evaluating the effects of MATOB on fetal neurodevelopment.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Mitochondria-focused gene expression profile reveals common pathways and CPT1B dysregulation in both rodent stress model and human subjects with PTSD.

Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (P<0.007) and in the blood (P<0.01) of stressed rats compared with non-stressed controls. In human subjects with (n=28) or without PTSD (n=31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P=0.0027, false discovery rate (FDR)=0.043) and PPAR (P=0.006, FDR=0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.

Network analysis identifies SOD2 mRNA as a potential biomarker for Parkinson's disease.

Increasing evidence indicates that Parkinson's disease (PD) and type 2 diabetes (T2DM) share dysregulated molecular networks. We identified 84 genes shared between PD and T2DM from curated disease-gene databases. Nitric oxide biosynthesis, lipid and carbohydrate metabolism, insulin secretion and inflammation were identified as common dysregulated pathways. A network prioritization approach was implemented to rank genes according to their distance to seed genes and their involvement in common biological pathways. Quantitative polymerase chain reaction assays revealed that a highly ranked gene, superoxide dismutase 2 (SOD2), is upregulated in PD patients compared to healthy controls in 192 whole blood samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Diagnostic and Prognostic Biomarkers in Parkinson's disease (PROBE). The results from this study reinforce the idea that shared molecular networks between PD and T2DM provides an additional source of biologically meaningful biomarkers. Evaluation of this biomarker in de novo PD patients and in a larger prospective longitudinal study is warranted.