My Recent Publications

Fibrocyte accumulation in the lungs of cystic fibrosis patients.

My Recent Publications - Wed, 2020-07-01 06:57
Related Articles

Fibrocyte accumulation in the lungs of cystic fibrosis patients.

J Cyst Fibros. 2020 Jun 24;:

Authors: Kasam RK, Gajjala PR, Jegga AG, Courtney JA, Randell SH, Kramer EL, Clancy JP, Madala SK

Abstract
BACKGROUND: Cystic fibrosis (CF) patients develop severe lung disease including chronic airway infections, neutrophilic inflammation, and progressive fibrotic remodeling in airways. However, cellular and molecular processes that regulate excessive collagen deposition in airways in these patients remain unclear. Fibrocytes are bone marrow (BM)-derived mesenchymal cells that express the hematopoietic cell marker CD45, and mesenchymal cell markers and implicated in collagen deposition in several fibrotic diseases. It is unknown whether fibrocytes accumulate in the lungs of CF patients, so the current study evaluates the presence of fibrocytes in the fibrotic lesions of airways in explanted CF lungs compared to non-CF unused donor lungs (control).
METHODS: We used immunofluorescence staining to determine if fibrocytes accumulate in explanted CF lungs compared to healthy donor lungs. Simultaneously, we evaluated cells collected by bronchoalveolar lavage (BAL) in CF patients using multi-color flow cytometry. Finally, we analyzed transcripts differentially expressed in fibrocytes isolated from the explanted CF lungs compared to control to assess fibrocyte-specific pro-fibrotic gene networks.
RESULTS: Our findings demonstrate fibrocyte accumulation in CF lungs compared to non-CF lungs. Additionally, fibrocytes were detected in the BAL of all CF children. Transcriptomic analysis of fibrocytes identified dysregulated genes associated with fibrotic remodeling in CF lungs.
CONCLUSIONS: With significantly increased fibrocytes that show increased expression of pro-fibrotic gene transcripts compared to control, our findings suggest an intervention for fibrotic remodeling as a potential therapeutic target in CF.

PMID: 32593509 [PubMed - as supplied by publisher]

Nuclear receptor binding factor 2 (NRBF2) is required for learning and memory.

My Recent Publications - Fri, 2020-05-01 08:07
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Nuclear receptor binding factor 2 (NRBF2) is required for learning and memory.

Lab Invest. 2020 Apr 29;:

Authors: Ouyang X, Ahmad I, Johnson MS, Redmann M, Craver J, Wani WY, Benavides GA, Chacko B, Li P, Young M, Jegga AG, Darley-Usmar V, Zhang J

Abstract
The mechanisms which underlie defects in learning and memory are a major area of focus with the increasing incidence of Alzheimer's disease in the aging population. The complex genetically-controlled, age-, and environmentally-dependent onset and progression of the cognitive deficits and neuronal pathology call for better understanding of the fundamental biology of the nervous system function. In this study, we focus on nuclear receptor binding factor-2 (NRBF2) which modulates the transcriptional activities of retinoic acid receptor α and retinoid X receptor α, and the autophagic activities of the BECN1-VPS34 complex. Since both transcriptional regulation and autophagic function are important in supporting neuronal function, we hypothesized that NRBF2 deficiency may lead to cognitive deficits. To test this, we developed a new mouse model with nervous system-specific knockout of Nrbf2. In a series of behavioral assessment, we demonstrate that NRBF2 knockout in the nervous system results in profound learning and memory deficits. Interestingly, we did not find deficits in autophagic flux in primary neurons and the autophagy deficits were minimal in the brain. In contrast, RNAseq analyses have identified altered expression of genes that have been shown to impact neuronal function. The observation that NRBF2 is involved in learning and memory suggests a new mechanism regulating cognition involving the role of this protein in regulating networks related to the function of retinoic acid receptors, protein folding, and quality control.

PMID: 32350405 [PubMed - as supplied by publisher]

Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction through Disruption of LXRα Signaling in Macrophages.

My Recent Publications - Sun, 2020-03-15 07:27

Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction through Disruption of LXRα Signaling in Macrophages.

Cardiovasc Res. 2020 Mar 14;:

Authors: Li Y, Deng S, Wang X, Huang W, Chen J, Robbins N, Mu X, Essandoh K, Peng T, Jegga AG, Rubinstein J, Adams DE, Wang Y, Peng J, Fan GC

Abstract
AIM: Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown.
METHODS AND RESULTS: Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after LPS injection, when compared to wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly downregulated genes in KO-BMDMs were modulated by LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls.
CONCLUSION: This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRα signaling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction.
TRANSLATIONAL PERSPECTIVE: Better understanding on the interaction between inflammatory responses and cardiac health is prominent for the development of safer and more efficacious therapies for heart failure patients. The present study, using both acute (LPS) and chronic (high-fat diet) inflammation models, reiterated the adverse effects of abnormal macrophages activation on cardiac function. Our Sectm1a knockout mouse model showed exacerbated cardiac and systemic inflammatory responses, resulting in further aggravation of contractile dysfunction on the heart after endotoxin challenge. We also demonstrated Sectm1a as a new regulator of macrophage function through LXRα pathway. These data suggest a novel approach to regulate macrophage-elicited inflammation.

PMID: 32170929 [PubMed - as supplied by publisher]

Systems biology-based approaches to summarize and identify novel genes and pathways associated with acute and chronic postsurgical pain.

My Recent Publications - Sat, 2020-02-15 07:07

Systems biology-based approaches to summarize and identify novel genes and pathways associated with acute and chronic postsurgical pain.

J Clin Anesth. 2020 Feb 11;62:109738

Authors: Chidambaran V, Ashton M, Martin LJ, Jegga AG

Abstract
STUDY OBJECTIVE: To employ systems biology-based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain.
DESIGN: Informed systems biology based integrative computational analyses.
SETTING: Pediatric research and teaching institution.
INTERVENTIONS: Pubmed search (01/01/2001-10/31/2017) was performed to identify "training" genes associated with postoperative pain in humans. Candidate genes were identified and prioritized using Toppgene suite, based on functional enrichment using several gene ontology annotations, and curated gene sets associated with mouse phenotype-knockout studies.
MEASUREMENTS: Computationally top-ranked candidate genes and literature-curated genes were included in pathway enrichment analyses. Hierarchical clustering was used to visualize select functional enrichment results between the two phenotypes.
MAIN RESULTS: Literature review identified 38 training genes associated with postoperative pain and 31 with CPSP. We identified 2610 prioritized novel candidate genes likely associated with acute and chronic postsurgical pain, the top 10th percentile jointly enriched (p 0.05; Benjamini-Hochberg correction) several pathways, topmost being cAMP response element-binding protein and ion channel pathways. Heat maps demonstrated enrichment of inflammatory/drug metabolism processes in acute postoperative pain and immune mechanisms in CPSP.
CONCLUSION: High interindividual variability in pain responses immediately after surgery and risk for CPSP suggests genetic susceptibility. Lack of large homogenous sample sizes have led to underpowered genetic association studies. Systems biology can be leveraged to integrate genetic-level data with biologic processes to generate prioritized candidate gene lists and understand novel biological pathways involved in acute postoperative pain and CPSP. Such data would be key to informing future polygenic studies with targeted genome wide profiling. This study demonstrates the utility of functional annotation - based prioritization and enrichment approaches and identifies novel genes and unique/shared biological processes involved in acute and chronic postoperative pain. Results provide framework for future targeted genetic profiling of CPSP risk, to enable preventive and therapeutic approaches.

PMID: 32058259 [PubMed - as supplied by publisher]

Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against oxidative damage.

My Recent Publications - Sat, 2020-02-15 07:07

Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against oxidative damage.

Redox Biol. 2020 Feb 06;:101453

Authors: Deng S, Essandoh K, Wang X, Li Y, Huang W, Chen J, Peng J, Jiang DS, Mu X, Wang C, Peng T, Guan JL, Wang Y, Jegga A, Huang K, Fan GC

Abstract
Currently, most antioxidants do not show any favorable clinical outcomes in reducing myocardial ischemia-reperfusion (I/R) injury, suggesting an urgent need for exploring a new regulator of redox homeostasis in I/R hearts. Here, using heart-specific transgenic (TG) and knockdown (KD) mouse models, tumor susceptibility gene 101 (Tsg101) is defined as a novel cardiac-protector against I/R-triggered oxidative stress. RNA sequencing and bioinformatics data surprisingly reveal that most upregulated genes in Tsg101-TG hearts are transcribed by Nrf2. Accordingly, pharmacological inhibition of Nrf2 offsets Tsg101-elicited cardio-protection. Mechanistically, Tsg101 interacts with SQSTM1/p62 through its PRR domain, and promotes p62 aggregation, leading to recruitment of Keap1 for degradation by autophagosomes and release of Nrf2 to the nucleus. Furthermore, knockout of p62 abrogates Tsg101-induced cardio-protective effects during I/R. Hence, our findings uncover a previously unrecognized role of Tsg101 in the regulation of p62/Keap1/Nrf2 signaling cascades and provide a new strategy for the treatment of ischemic heart disease.

PMID: 32057709 [PubMed - as supplied by publisher]

The Cumulative Influence of Inflammatory Response Genetic Variation on Long-Term Neurobehavioral Outcomes following Pediatric Traumatic Brain Injury Relative to Orthopedic Injury: An Exploratory Polygenic Risk Score.

My Recent Publications - Fri, 2020-02-07 06:00
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The Cumulative Influence of Inflammatory Response Genetic Variation on Long-Term Neurobehavioral Outcomes following Pediatric Traumatic Brain Injury Relative to Orthopedic Injury: An Exploratory Polygenic Risk Score.

J Neurotrauma. 2020 Feb 05;:

Authors: Treble-Barna A, Pilipenko V, Wade SL, Jegga A, Yeates KO, Taylor HG, Martin LJ, Kurowski BG

Abstract
The addition of genetic factors to prognostic models of neurobehavioral recovery following pediatric traumatic brain injury (TBI) may account for unexplained heterogeneity in outcomes. The present study examined the cumulative influence of candidate genes involved in the inflammatory response on long-term neurobehavioral recovery in children with early childhood TBI relative to children with orthopedic injuries (OI). Participants were drawn from a prospective, longitudinal study evaluating outcomes of children who sustained TBI (n = 67) or OI (n = 68) between age 3-7 years. Parents completed ratings of child executive function and behavior at an average of 6.8 years after injury. Exploratory unweighted and weighted polygenic risk scores (PRS) were constructed from single nucleotide polymorphisms (SNPs) across candidate inflammatory response genes (i.e., ACE, BDNF, IL1RN, and NT5E) that showed nominal (p ≤ .20) associations with outcomes in the TBI group. Linear regression models tested the PRS x injury group (TBI vs OI) interaction term and post hoc analyses examined the effect of PRS within each injury group. Higher inflammatory response PRS were associated with more executive dysfunction and behavior problems in children with TBI but not in children with OI. The cumulative influence of inflammatory response genes as measured by PRS explained additional variance in long-term neurobehavioral outcomes, over and above well-established predictors and single candidate SNPs tested individually. The results suggest that some of the unexplained heterogeneity in long-term neurobehavioral outcomes following pediatric TBI may be attributable to a child's genetic predisposition for a greater or lesser inflammatory response to TBI.

PMID: 32024452 [PubMed - as supplied by publisher]

Comprehensive anatomic ontologies for lung development: A comparison of alveolar formation and maturation within mouse and human lung.

My Recent Publications - Mon, 2019-10-28 17:48
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Comprehensive anatomic ontologies for lung development: A comparison of alveolar formation and maturation within mouse and human lung.

J Biomed Semantics. 2019 Oct 24;10(1):18

Authors: Pan H, Deutsch GH, Wert SE, Ontology Subcommittee, NHLBI Molecular Atlas of Lung Development Program Consortium

Abstract
BACKGROUND: Although the mouse is widely used to model human lung development, function, and disease, our understanding of the molecular mechanisms involved in alveolarization of the peripheral lung is incomplete. Recently, the Molecular Atlas of Lung Development Program (LungMAP) was funded by the National Heart, Lung, and Blood Institute to develop an integrated open access database (known as BREATH) to characterize the molecular and cellular anatomy of the developing lung. To support this effort, we designed detailed anatomic and cellular ontologies describing alveolar formation and maturation in both mouse and human lung.
DESCRIPTION: While the general anatomic organization of the lung is similar for these two species, there are significant variations in the lung's architectural organization, distribution of connective tissue, and cellular composition along the respiratory tract. Anatomic ontologies for both species were constructed as partonomic hierarchies and organized along the lung's proximal-distal axis into respiratory, vascular, neural, and immunologic components. Terms for developmental and adult lung structures, tissues, and cells were included, providing comprehensive ontologies for application at varying levels of resolution. Using established scientific resources, multiple rounds of comparison were performed to identify common, analogous, and unique terms that describe the lungs of these two species. Existing biological and biomedical ontologies were examined and cross-referenced to facilitate integration at a later time, while additional terms were drawn from the scientific literature as needed. This comparative approach eliminated redundancy and inconsistent terminology, enabling us to differentiate true anatomic variations between mouse and human lungs. As a result, approximately 300 terms for fetal and postnatal lung structures, tissues, and cells were identified for each species.
CONCLUSION: These ontologies standardize and expand current terminology for fetal and adult lungs, providing a qualitative framework for data annotation, retrieval, and integration across a wide variety of datasets in the BREATH database. To our knowledge, these are the first ontologies designed to include terminology specific for developmental structures in the lung, as well as to compare common anatomic features and variations between mouse and human lungs. These ontologies provide a unique resource for the LungMAP, as well as for the broader scientific community.

PMID: 31651362 [PubMed - in process]

Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR.

My Recent Publications - Wed, 2019-07-10 12:31

Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR.

Sci Rep. 2019 Jul 08;9(1):9808

Authors: Huang Y, Arora K, Mun KS, Yang F, Moon C, Yarlagadda S, Jegga A, Weaver T, Naren AP

Abstract
The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal co-chaperone, DNAJB9, which can directly interact with CFTR. For both WT- and ΔF508 (deletion of phenylalanine at position 508, the most common CF-causing mutant)-CFTR, knockdown of DNAJB9 by siRNA increased their expression levels on the cell surface and, consequently, upregulated their function. Furthermore, genetic ablation of DNAJB9 in WT mice increased CFTR expression and enhanced CFTR-dependent fluid secretion in enteroids. Importantly, DNAJB9 deficiency upregulated enteroids' fluid secretion in CF mice (homozygous for ΔF508), and silencing one allele of DNAJB9 is sufficient to rescue ΔF508-CFTR in vitro and in vivo, suggesting that DNAJB9 may be a rate-limiting factor in CFTR ERAD pathway. Our studies identified the first ER luminal co-chaperone involved in CFTR ERAD, and DNAJB9 could be a novel therapeutic target for CF.

PMID: 31285458 [PubMed - in process]

Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach.

My Recent Publications - Fri, 2019-06-14 12:19

Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach.

Front Genet. 2019;10:481

Authors: Kurowski BG, Treble-Barna A, Pilipenko V, Wade SL, Yeates KO, Taylor HG, Martin LJ, Jegga AG

Abstract
Objectives: To test whether genetic associations with behavioral outcomes after early childhood traumatic brain injury (TBI) are enriched for biologic pathways underpinning neurocognitive and behavioral networks. Design: Cross-sectional evaluation of the association of genetic factors with early (~ 6 months) and long-term (~ 7 years) post-TBI behavioral outcomes. We combined systems biology and genetic association testing methodologies to identify biologic pathways associated with neurocognitive and behavior outcomes after TBI. We then evaluated whether genes/single nucleotide polymorphism (SNPs) associated with these biologic pathways were more likely to demonstrate a relationship (i.e., enrichment) with short and long-term behavioral outcomes after early childhood TBI compared to genes/SNPs not associated with these biologic pathways. Setting: Outpatient research setting. Participants:140 children, ages 3-6:11 years at time of injury, admitted for a TBI or orthopedic injury (OI). Interventions: Not Applicable. Main Outcome Measures: Child behavior checklist total problems T score. Results: Systems biology methodology identified neuronal systems and neurotransmitter signaling (Glutamate receptor, dopamine, serotonin, and calcium signaling), inflammatory response, cell death, immune systems, and brain development as important biologic pathways to neurocognitive and behavioral outcomes after TBI. At 6 months post injury, the group (TBI versus OI) by polymorphism interaction was significant when the aggregate signal from the highest ranked 40% of case gene associations was compared to the control set of genes. At ~ 7 years post injury, the selected polymorphisms had a significant main effect after controlling for injury type when the aggregate signal from the highest ranked 10% of the case genes were compared to the control set of genes Conclusions: Findings demonstrate the promise of applying a genomics approach, informed by systems biology, to understanding behavioral recovery after pediatric TBI. A mixture of biologic pathways and processes are associated with behavioral recovery, specifically genes associated with cell death, inflammatory response, neurotransmitter signaling, and brain development. These results provide insights into the complex biology of TBI recovery.

PMID: 31191606 [PubMed]

Dysregulation of Mesenchymal Cell Survival Pathways in Severe Fibrotic Lung Disease: The Effect of Nintedanib Therapy.

My Recent Publications - Tue, 2019-06-04 06:18

Dysregulation of Mesenchymal Cell Survival Pathways in Severe Fibrotic Lung Disease: The Effect of Nintedanib Therapy.

Front Pharmacol. 2019;10:532

Authors: Kasam RK, Reddy GB, Jegga AG, Madala SK

Abstract
Impaired apoptotic clearance of myofibroblasts can result in the continuous expansion of scar tissue during the persistent injury in the lung. However, the molecular and cellular mechanisms underlying the apoptotic clearance of multiple mesenchymal cells including fibrocytes, fibroblasts and myofibroblasts in severe fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) remain largely unknown. We analyzed the apoptotic pathways activated in mesenchymal cells of IPF and in a mouse model of TGFα-induced pulmonary fibrosis. We found that fibrocytes and myofibroblasts in fibrotic lung lesions have acquired resistance to Fas-induced apoptosis, and an FDA-approved anti-fibrotic agent, nintedanib, effectively induced apoptotic cell death in both. In support, comparative gene expression analyses suggest that apoptosis-linked gene networks similarly dysregulated in both IPF and a mouse model of TGFα-induced pulmonary fibrosis. TGFα mice treated with nintedanib show increased active caspase 3-positive cells in fibrotic lesions and reduced fibroproliferation and collagen production. Further, the long-term nintedanib therapy attenuated fibrocyte accumulation, collagen deposition, and lung function decline during TGFα-induced pulmonary fibrosis. These results highlight the importance of inhibiting survival pathways and other pro-fibrotic processes in the various types of mesenchymal cells and suggest that the TGFα mouse model is relevant for testing of anti-fibrotic drugs either alone or in combination with nintedanib.

PMID: 31156440 [PubMed]

Transcriptomic Data Mining and Repurposing for Computational Drug Discovery.

My Recent Publications - Fri, 2018-12-14 15:42
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Transcriptomic Data Mining and Repurposing for Computational Drug Discovery.

Methods Mol Biol. 2019;1903:73-95

Authors: Wang Y, Yella J, Jegga AG

Abstract
Conventional drug discovery in general is costly and time-consuming with extremely low success and relatively high attrition rates. The disparity between high cost of drug discovery and vast unmet medical needs resulted in advent of an increasing number of computational approaches that can "connect" disease with a candidate therapeutic. This includes computational drug repurposing or repositioning wherein the goal is to discover a new indication for an approved drug. Computational drug discovery approaches that are commonly used are similarity-based wherein network analysis or machine learning-based methods are used. One such approach is matching gene expression signatures from disease to those from small molecules, commonly referred to as connectivity mapping. In this chapter, we will focus on how publicly available existing transcriptomic data from diseases can be reused to identify novel candidate therapeutics and drug repositioning candidates. To elucidate these, we will present two case studies: (1) using transcriptional signature similarity or positive correlation to identify novel small molecules that are similar to an approved drug and (2) identifying candidate therapeutics via reciprocal connectivity or negative correlation between transcriptional signatures from a disease and small molecule.

PMID: 30547437 [PubMed - in process]

Wilms' tumor 1 drives fibroproliferation and myofibroblast transformation in severe fibrotic lung disease.

My Recent Publications - Fri, 2018-08-24 08:27
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Wilms' tumor 1 drives fibroproliferation and myofibroblast transformation in severe fibrotic lung disease.

JCI Insight. 2018 Aug 23;3(16):

Authors: Sontake V, Kasam RK, Sinner D, Korfhagen TR, Reddy GB, White ES, Jegga AG, Madala SK

Abstract
Wilms' tumor 1 (WT1) is a critical transcriptional regulator of mesothelial cells during lung development but is downregulated in postnatal stages and adult lungs. We recently showed that WT1 is upregulated in both mesothelial cells and mesenchymal cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal fibrotic lung disease. Although WT1-positive cell accumulation leading to severe fibrotic lung disease has been studied, the role of WT1 in fibroblast activation and pulmonary fibrosis remains elusive. Here, we show that WT1 functions as a positive regulator of fibroblast activation, including fibroproliferation, myofibroblast transformation, and extracellular matrix (ECM) production. Chromatin immunoprecipitation experiments indicate that WT1 binds directly to the promoter DNA sequence of α-smooth muscle actin (αSMA) to induce myofibroblast transformation. In support, the genetic lineage tracing identifies WT1 as a key driver of mesothelial-to-myofibroblast and fibroblast-to-myofibroblast transformation. Importantly, the partial loss of WT1 was sufficient to attenuate myofibroblast accumulation and pulmonary fibrosis in vivo. Further, our coculture studies show that WT1 upregulation leads to non-cell autonomous effects on neighboring cells. Thus, our data uncovered a pathogenic role of WT1 in IPF by promoting fibroblast activation in the peripheral areas of the lung and as a target for therapeutic intervention.

PMID: 30135315 [PubMed - as supplied by publisher]

Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.

My Recent Publications - Thu, 2018-08-23 07:57
Related Articles

Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.

Oncotarget. 2018 Jul 27;9(58):31214-31230

Authors: Hankey W, Chen Z, Bergman MJ, Fernandez MO, Hancioglu B, Lan X, Jegga AG, Zhang J, Jin VX, Aronow BJ, Wang Q, Groden J

Abstract
Mutation of the APC gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling. 289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway.

PMID: 30131849 [PubMed]

An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.

My Recent Publications - Thu, 2018-06-21 06:32

An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.

Cell Rep. 2018 Jun 19;23(12):3607-3620

Authors: Peng J, Li Y, Wang X, Deng S, Holland J, Yates E, Chen J, Gu H, Essandoh K, Mu X, Wang B, McNamara RK, Peng T, Jegga AG, Liu T, Nakamura T, Huang K, Perez-Tilve D, Fan GC

Abstract
Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a negative regulator of adipocyte function. Deletion of Hsp20 enhances non-shivering thermogenesis and suppresses inflammatory responses, leading to improvement of glucose and lipid metabolism under both chow diet and high-fat diet conditions. Mechanistically, Hsp20 controls adipocyte function by interacting with the subunit of the ubiquitin ligase complex, F-box only protein 4 (FBXO4), and regulating the ubiquitin-dependent degradation of peroxisome proliferation activated receptor gamma (PPARγ). Indeed, Hsp20 deficiency mimics and enhances the pharmacological effects of the PPARγ agonist rosiglitazone. Together, our findings suggest a role of Hsp20 in mediating adipocyte function by linking β-adrenergic signaling to PPARγ activity.

PMID: 29925002 [PubMed - in process]

Novel phenotype-disease matching tool for rare genetic diseases.

My Recent Publications - Thu, 2018-06-14 06:22
Related Articles

Novel phenotype-disease matching tool for rare genetic diseases.

Genet Med. 2018 Jun 12;:

Authors: Chen J, Xu H, Jegga A, Zhang K, White PS, Zhang G

Abstract
PURPOSE: To improve the accuracy of matching rare genetic diseases based on patient's phenotypes.
METHODS: We introduce new methods to prioritize diagnosis of genetic diseases based on integrated semantic similarity (method 1) and ontological overlap (method 2) between the phenotypes expressed by a patient and phenotypes annotated to known diseases.
RESULTS: We evaluated the performance of our methods by two sets of simulated data and one set of patient's data derived from electronic health records. We demonstrated that the two methods achieved significantly improved performance compared with previous methods in correctly prioritizing candidate diseases in all of the three sets. Our methods are freely available as a web application ( https://gddp.
RESEARCH: cchmc.org/ ) to aid diagnosis of genetic diseases.
CONCLUSION: Our methods can capture the diagnostic information embedded in the phenotype ontology, consider all phenotypes exhibited by a patient, and are more robust than the existing methods when phenotypes are incorrectly or imprecisely specified. These methods can assist the diagnosis of rare genetic diseases and help the interpretation of the results of DNA tests.

PMID: 29895857 [PubMed - as supplied by publisher]

GNOMICS: A one-stop shop for biomedical and genomic data.

My Recent Publications - Tue, 2018-06-12 08:32

GNOMICS: A one-stop shop for biomedical and genomic data.

AMIA Jt Summits Transl Sci Proc. 2018;2017:118-123

Authors: Kronk CJ, Jegga A

Abstract
The World Wide Web is an indispensable tool for biomedical researchers who are striving to understand the molecular basis of phenotype. However, it presents challenges in the form of proliferation of data resources, with heterogeneity ranging from their content to functionality to interfaces. This often frustrates researchers who must visit multiple sites, become familiar with their interfaces, and learn how to use them to extract knowledge. Even then, one may never feel sure that they have tracked down all needed information. We envision addressing this challenge with GNOMICS (Genomic Nomenclature Omnibus and Multifaceted Informatics and Computational Suite), a suite with both a programmatic interface and a GUI. GNOMICS allows for extensible biomedical functionality, including identifier conversion, pathway enrichment, sequence alignment, and reference gathering, among others. It combines usage of other biological and chemical database application programming interfaces (APIs) to deliver uniform data which can be further manipulated and parsed.

PMID: 29888054 [PubMed]

Characterizing drug-related adverse events by joint analysis of biomedical and genomic data: A case study of drug-induced pulmonary fibrosis.

My Recent Publications - Tue, 2018-06-12 08:32

Characterizing drug-related adverse events by joint analysis of biomedical and genomic data: A case study of drug-induced pulmonary fibrosis.

AMIA Jt Summits Transl Sci Proc. 2018;2017:91-97

Authors: Jiang A, Jegga AG

Abstract
Spontaneous reporting systems such as the FDA's adverse event reporting system (FAERS) present a great resource to mine for and analyze real-world medication usage. Our study is based on a central premise that FAERS captures unsuspected drug-related adverse events (AEs). Since drug-related AEs result for several reasons, no single approach will be able to predict the entire gamut of AEs. A fundamental premise of systems biology is that a full understanding of a biological process or phenotype (e.g., drug-related AE) requires that all the individual elements be studied in conjunction with one another. We therefore hypothesize that integrative analysis of FAERS-based drug-related AEs with the transcriptional signatures from disease models and drug treatments can lead to the generation of unbiased hypotheses for drug-induced AE-modulating mechanisms of action as well as drug combinations that may target those mechanisms. We test this hypothesis using drug-induced pulmonary fibrosis (DIPF) as a proof-of-concept study.

PMID: 29888048 [PubMed]

Changing Trends in Computational Drug Repositioning.

My Recent Publications - Fri, 2018-06-08 06:42
Related Articles

Changing Trends in Computational Drug Repositioning.

Pharmaceuticals (Basel). 2018 Jun 05;11(2):

Authors: Yella JK, Yaddanapudi S, Wang Y, Jegga AG

Abstract
Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated-"The most fruitful basis for the discovery of a new drug is to start with an old drug". However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of "serendipity", discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules-pharmacologically relevant sub-networks of biomolecules and/or pathways-from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning.

PMID: 29874824 [PubMed]

The nuclear DEK interactome supports multi-functionality: "The DEK Interactome".

My Recent Publications - Tue, 2017-10-31 06:12

The nuclear DEK interactome supports multi-functionality: "The DEK Interactome".

Proteins. 2017 Oct 30;:

Authors: Smith EA, Krumpelbeck EF, Jegga AG, Prell M, Matrka MM, Kappes F, Greis KD, Ali AM, Meetei AR, Wells SI

Abstract
DEK is an oncoprotein that is overexpressed in many forms of cancer and participates in numerous cellular pathways. Of these different pathways, relevant interacting partners and functions of DEK are well described in regard to the regulation of chromatin structure, epigenetic marks, and transcription. Most of this understanding was derived by investigating DNA-binding and chromatin processing capabilities of the oncoprotein. To facilitate the generation of mechanism-driven hypotheses regarding DEK activities in underexplored areas, we have developed the first DEK interactome model using tandem-affinity purification and mass spectrometry. With this approach we identify IMPDH2, DDX21, and RPL7a as novel DEK binding partners, hinting at new roles for the oncogene in de novo nucleotide biosynthesis and ribosome formation. Additionally, a hydroxyurea-specific interaction with RPA was observed, suggesting that a DEK-RPA complex may form in response to DNA replication fork stalling. Taken together, these findings highlight diverse activities for DEK across cellular pathways and support a model wherein this molecule performs a plethora of functions. This article is protected by copyright. All rights reserved.

PMID: 29082557 [PubMed - as supplied by publisher]

Unsupervised gene expression analyses identify IPF-severity correlated signatures, associated genes and biomarkers.

My Recent Publications - Tue, 2017-10-24 08:50

Unsupervised gene expression analyses identify IPF-severity correlated signatures, associated genes and biomarkers.

BMC Pulm Med. 2017 Oct 20;17(1):133

Authors: Wang Y, Yella J, Chen J, McCormack FX, Madala SK, Jegga AG

Abstract
BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a fatal fibrotic lung disease occurring predominantly in middle-aged and older adults. The traditional diagnostic classification of IPF is based on clinical, radiological, and histopathological features. However, the considerable heterogeneity in IPF presentation suggests that differences in gene expression profiles can help to characterize and distinguish disease severity.
METHODS: We used data-driven unsupervised clustering analysis, combined with a knowledge-based approach to identify and characterize IPF subgroups.
RESULTS: Using transcriptional profiles on lung tissue from 131 patients with IPF/UIP and 12 non-diseased controls, we identified six subgroups of IPF that generally correlated with the disease severity and lung function decline. Network-informed clustering identified the most severe subgroup of IPF that was enriched with genes regulating inflammatory processes, blood pressure and branching morphogenesis of the lung. The differentially expressed genes in six subgroups of IPF compared to healthy control include transcripts of extracellular matrix, epithelial-mesenchymal cell cross-talk, calcium ion homeostasis, and oxygen transport. Further, we compiled differentially expressed gene signatures to identify unique gene clusters that can segregate IPF from normal, and severe from mild IPF. Additional validations of these signatures were carried out in three independent cohorts of IPF/UIP. Finally, using knowledge-based approaches, we identified several novel candidate genes which may also serve as potential biomarkers of IPF.
CONCLUSIONS: Discovery of unique and redundant gene signatures for subgroups in IPF can be greatly facilitated through unsupervised clustering. Findings derived from such gene signatures may provide insights into pathogenesis of IPF and facilitate the development of clinically useful biomarkers.

PMID: 29058630 [PubMed - in process]

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