Publications by authors named "Ahwan Pandey"

18 Publications

  • Page 1 of 1

Nutlin-Induced Apoptosis Is Specified by a Translation Program Regulated by PCBP2 and DHX30.

Cell Rep 2020 03;30(13):4355-4369.e6

Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy. Electronic address:

Activation of p53 by the small molecule Nutlin can result in a combination of cell cycle arrest and apoptosis. The relative strength of these events is difficult to predict by classical gene expression analysis, leaving uncertainty as to the therapeutic benefits. In this study, we report a translational control mechanism shaping p53-dependent apoptosis. Using polysome profiling, we establish Nutlin-induced apoptosis to associate with the enhanced translation of mRNAs carrying multiple copies of an identified 3' UTR CG-rich motif mediating p53-dependent death (CGPD-motif). We identify PCBP2 and DHX30 as CGPD-motif interactors. We find that in cells undergoing persistent cell cycle arrest in response to Nutlin, CGPD-motif mRNAs are repressed by the PCBP2-dependent binding of DHX30 to the motif. Upon DHX30 depletion in these cells, the translation of CGPD-motif mRNAs increases, and the response to Nutlin shifts toward apoptosis. Instead, DHX30 inducible overexpression in SJSA1 cells leads to decreased translation of CGPD-motif mRNAs.
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http://dx.doi.org/10.1016/j.celrep.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182397PMC
March 2020

Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome.

Cell Rep 2019 11;29(7):1893-1908.e4

Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80302, USA. Electronic address:

People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments. Furthermore, measurement of interferon-inducible phosphorylation events revealed widespread hypersensitivity to interferon-α in DS, with cell-type-specific variations in downstream intracellular signaling. Mechanistically, this could be explained by overexpression of the interferon receptors encoded on chromosome 21, as demonstrated by increased IFNAR1 surface expression in all immune lineages tested. These results point to interferon-driven immune dysregulation as a likely contributor to the developmental and clinical hallmarks of DS.
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http://dx.doi.org/10.1016/j.celrep.2019.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871766PMC
November 2019

Going to extremes: determinants of extraordinary response and survival in patients with cancer.

Nat Rev Cancer 2019 06;19(6):339-348

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients, and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome and make recommendations for future studies on these intriguing patients.
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http://dx.doi.org/10.1038/s41568-019-0145-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255796PMC
June 2019

Sex and puberty-related differences in metabolomic profiles associated with adiposity measures in youth with obesity.

Metabolomics 2019 05 3;15(5):75. Epub 2019 May 3.

Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.

Background: Specific patterns of metabolomic profiles relating to cardiometabolic disease are associated with increased weight in adults. In youth with obesity, metabolomic data are sparse and associations with adiposity measures unknown.

Objectives: Primary, to determine associations between adiposity measures and metabolomic profiles with increased cardiometabolic risks in youth with obesity. Secondary, to stratify associations by sex and puberty.

Methods: Participants were from COBRA (Childhood Overweight BioRepository of Australia; a paediatric cohort with obesity). Adiposity measures (BMI, BMI z-score, %truncal and %whole body fat, waist circumference and waist/height ratio), puberty staging and NMR metabolomic profiles from serum were assessed. Statistics included multivariate analysis (principal component analysis, PCA) and multiple linear regression models with false discovery rate adjustment.

Results: 214 participants had metabolomic profiles analyzed, mean age 11.9 years (SD ± 3.1), mean BMI z-score 2.49 (SD ± 0.24), 53% females. Unsupervised PCA identified no separable clusters of individuals. Positive associations included BMI z-score and phenylalanine, total body fat % and lipids in medium HDL, and waist circumference and tyrosine; negative associations included total body fat % and the ratio of docosahexaenoic acid/total fatty acids and histidine. Stratifying by sex and puberty, patterns of associations with BMI z-score in post-pubertal males included positive associations with lipid-, cholesterol- and triglyceride-content in VLDL lipoproteins; total fatty acids; total triglycerides; isoleucine, leucine and glycoprotein acetyls.

Conclusion: In a paediatric cohort with obesity, increased adiposity measures, especially in post-pubertal males, were associated with distinct patterns in metabolomic profiles.
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http://dx.doi.org/10.1007/s11306-019-1537-yDOI Listing
May 2019

Survival Following Chemotherapy in Ovarian Clear Cell Carcinoma Is Not Associated with Pathological Misclassification of Tumor Histotype.

Clin Cancer Res 2019 07 9;25(13):3962-3973. Epub 2019 Apr 9.

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Purpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology.

Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( = 5) or had a very short time to progression ( = 5).

Results: The majority of mixed OCCC ( = 6, 85.7%) and a small proportion of pure OCCC ( = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified samples were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( = 0.0194 and 0.0395, respectively). Mutations in , and were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations.

Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3691DOI Listing
July 2019

Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer.

Nat Commun 2019 03 20;10(1):1295. Epub 2019 Mar 20.

Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia.

ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.
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http://dx.doi.org/10.1038/s41467-019-09312-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426934PMC
March 2019

SIX2 Mediates Late-Stage Metastasis via Direct Regulation of and Induction of a Cancer Stem Cell Program.

Cancer Res 2019 02 3;79(4):720-734. Epub 2019 Jan 3.

Integrated Physiology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the Srr2 enhancer, promoting expression and downstream expression of , which are both key pluripotency factors. Regulation of by Six2 enhanced cancer stem cell properties and increased metastatic colonization. and expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells. http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586234PMC
February 2019

ΔNp63α Suppresses TGFB2 Expression and RHOA Activity to Drive Cell Proliferation in Squamous Cell Carcinomas.

Cell Rep 2018 09;24(12):3224-3236

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Functional Genomics Facility, University of Colorado School of Medicine, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80203, USA. Electronic address:

The transcriptional repressor ΔNp63α is a potent oncogene widely overexpressed in squamous cell carcinomas (SCCs) of diverse tissue origins, where it promotes malignant cell proliferation and survival. We report here the results of a genome-wide CRISPR screen to identify pathways controlling ΔNp63α-dependent cell proliferation, which revealed that the small GTPase RHOA blocks cell division upon ΔNp63α knockdown. After ΔNp63α depletion, RHOA activity is increased, and cells undergo RHOA-dependent proliferation arrest along with transcriptome changes indicative of increased TGF-β signaling. Mechanistically, ΔNp63α represses transcription of TGFB2, which induces a cell cycle arrest that is partially dependent on RHOA. Ectopic TGFB2 activates RHOA and impairs SCC proliferation, and TGFB2 neutralization restores cell proliferation during ΔNp63α depletion. Genomic data from tumors demonstrate inactivation of RHOA and the TGFBR2 receptor and ΔNp63α overexpression in more than 80% of lung SCCs. These results reveal a signaling pathway controlling SCC proliferation that is potentially amenable to pharmacological intervention.
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http://dx.doi.org/10.1016/j.celrep.2018.08.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219633PMC
September 2018

Zinc Finger Protein 521 Regulates Early Hematopoiesis through Cell-Extrinsic Mechanisms in the Bone Marrow Microenvironment.

Mol Cell Biol 2018 09 15;38(17). Epub 2018 Aug 15.

Department of Biomedical Sciences, National Jewish Health, Denver, Colorado, USA

Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated genes () possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes bone marrow microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis. These results advance our understanding of ZFP521's role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.
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http://dx.doi.org/10.1128/MCB.00603-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094055PMC
September 2018

CDK8 Kinase Activity Promotes Glycolysis.

Cell Rep 2017 Nov;21(6):1495-1506

Linda Crnic Institute for Down Syndrome, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, CO 80309, USA. Electronic address:

Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancerous tissues. Despite its importance in cancer development, our understanding of mechanisms driving this form of metabolic reprogramming is incomplete. We report here an analysis of colorectal cancer cells engineered to carry a single point mutation in the active site of the Mediator-associated kinase CDK8, creating hypomorphic alleles sensitive to bulky ATP analogs. Transcriptome analysis revealed that CDK8 kinase activity is required for the expression of many components of the glycolytic cascade. CDK8 inhibition impairs glucose transporter expression, glucose uptake, glycolytic capacity and reserve, as well as cell proliferation and anchorage-independent growth, both in normoxia and hypoxia. Importantly, CDK8 impairment sensitizes cells to pharmacological glycolysis inhibition, a result reproduced with Senexin A, a dual inhibitor of CDK8/CDK19. Altogether, these results contribute to our understanding of CDK8 as an oncogene, and they justify investigations to target CDK8 in highly glycolytic tumors.
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http://dx.doi.org/10.1016/j.celrep.2017.10.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726794PMC
November 2017

Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation.

Sci Rep 2017 11 1;7(1):14818. Epub 2017 Nov 1.

Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, Colorado, 80045, USA.

Trisomy 21 (T21) causes Down syndrome (DS), but the mechanisms by which T21 produces the different disease spectrum observed in people with DS are unknown. We recently identified an activated interferon response associated with T21 in human cells of different origins, consistent with overexpression of the four interferon receptors encoded on chromosome 21, and proposed that DS could be understood partially as an interferonopathy. However, the impact of T21 on systemic signaling cascades in living individuals with DS is undefined. To address this knowledge gap, we employed proteomics approaches to analyze blood samples from 263 individuals, 165 of them with DS, leading to the identification of dozens of proteins that are consistently deregulated by T21. Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling. Importantly, people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-α) and pronounced complement consumption, resembling changes seen in type I interferonopathies and other autoinflammatory conditions. Therefore, these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation, and justify investigations to define the therapeutic value of immune-modulatory strategies in DS.
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http://dx.doi.org/10.1038/s41598-017-13858-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665944PMC
November 2017

Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity.

Genome Res 2017 10 13;27(10):1645-1657. Epub 2017 Sep 13.

Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.

The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53. We set out to address this problem by generating multiple genomic data sets for three different cancer cell lines, allowing the identification of distinct sets of TP53-regulated genes, from early transcriptional targets through to late targets controlled at the translational level. We found that although TP53 elicits vastly divergent signaling cascades across cell lines, it directly activates a core transcriptional program of ∼100 genes with diverse biological functions, regardless of cell type or cellular response to TP53 activation. This core program is associated with high-occupancy TP53 enhancers, high levels of paused RNA polymerases, and accessible chromatin. Interestingly, two different shRNA screens failed to identify a single TP53 target gene required for the anti-proliferative effects of TP53 during pharmacological activation in vitro. Furthermore, bioinformatics analysis of thousands of cancer genomes revealed that none of these core target genes are frequently inactivated in tumors expressing wild-type TP53. These results support the hypothesis that TP53 activates a genetically robust transcriptional program with highly distributed tumor suppressive functions acting in diverse cellular contexts.
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http://dx.doi.org/10.1101/gr.220533.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630028PMC
October 2017

A Kinase-Independent Role for Cyclin-Dependent Kinase 19 in p53 Response.

Mol Cell Biol 2017 07 15;37(13). Epub 2017 Jun 15.

Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado, USA

The human Mediator complex regulates RNA polymerase II transcription genome-wide. A general factor that regulates Mediator function is the four-subunit kinase module, which contains either cyclin-dependent kinase 8 (CDK8) or CDK19. Whereas CDK8 is linked to specific signaling cascades and oncogenesis, the cellular roles of its paralog, CDK19, are poorly studied. We discovered that osteosarcoma cells (SJSA) are naturally depleted of CDK8 protein. Whereas stable CDK19 knockdown was tolerated in SJSA cells, proliferation was reduced. Notably, proliferation defects were rescued upon the reexpression of wild-type or kinase-dead CDK19. Comparative RNA sequencing analyses showed reduced expression of mitotic genes and activation of genes associated with cholesterol metabolism and the p53 pathway in CDK19 knockdown cells. SJSA cells treated with 5-fluorouracil, which induces metabolic and genotoxic stress and activates p53, further implicated CDK19 in p53 target gene expression. To better probe the p53 response, SJSA cells (shCDK19 versus shCTRL) were treated with the p53 activator nutlin-3. Remarkably, CDK19 was required for SJSA cells to return to a proliferative state after nutlin-3 treatment, and this effect was kinase independent. These results implicate CDK19 as a regulator of p53 stress responses and suggest a role for CDK19 in cellular resistance to nutlin-3.
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http://dx.doi.org/10.1128/MCB.00626-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472832PMC
July 2017

Trisomy 21 consistently activates the interferon response.

Elife 2016 07 29;5. Epub 2016 Jul 29.

Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.

Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.
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http://dx.doi.org/10.7554/eLife.16220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012864PMC
July 2016

The TIP60 Complex Is a Conserved Coactivator of HIF1A.

Cell Rep 2016 06 16;16(1):37-47. Epub 2016 Jun 16.

Linda Crnic Institute for Down Syndrome, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address:

Hypoxia-inducible factors (HIFs) are critical regulators of the cellular response to hypoxia. Despite their established roles in normal physiology and numerous pathologies, the molecular mechanisms by which they control gene expression remain poorly understood. We report here a conserved role for the TIP60 complex as a HIF1 transcriptional cofactor in Drosophila and human cells. TIP60 (KAT5) is required for HIF1-dependent gene expression in fly cells and embryos and colorectal cancer cells. HIF1A interacts with and recruits TIP60 to chromatin. TIP60 is dispensable for HIF1A association with its target genes but is required for HIF1A-dependent chromatin modification and RNA polymerase II activation in hypoxia. In human cells, global analysis of HIF1A-dependent gene activity reveals that most HIF1A targets require either TIP60, the CDK8-Mediator complex, or both as coactivators for full expression in hypoxia. Thus, HIF1A employs functionally diverse cofactors to regulate different subsets of genes within its transcriptional program.
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http://dx.doi.org/10.1016/j.celrep.2016.05.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957981PMC
June 2016

Role of the host restriction factor APOBEC3 on papillomavirus evolution.

Virus Evol 2015 Jan 1;1(1). Epub 2015 Jan 1.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA; Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.

More than 270 different types of papillomaviruses have been discovered in a wide array of animal species. Despite the great diversity of papillomaviruses, little is known about the evolutionary processes that drive host tropism and the emergence of oncogenic genotypes. Although host defense mechanisms have evolved to interfere with various aspects of a virus life cycle, viruses have also coevolved copious strategies to avoid host antiviral restriction. Our and other studies have shown that the cytidine deaminase APOBEC3 family members edit HPV genomes and restrict virus infectivity. Thus, we hypothesized that host restriction by APOBEC3 served as selective pressure during papillomavirus evolution. To test this hypothesis, we analyzed the relative abundance of all dinucleotide sequences in full-length genomes of 274 papillomavirus types documented in the Papillomavirus Episteme database (PaVE). Here, we report that TC dinucleotides, the preferred target sequence of several human APOBEC3 proteins (hA3A, hA3B, hA3F, and hA3H), are highly depleted in papillomavirus genomes. Given that HPV infection is highly tissue-specific, the expression levels of APOBEC3 family members were analyzed. The basal expression levels of all APOBEC3 isoforms, excluding hA3B, are significantly higher in mucosal skin compared with cutaneous skin. Interestingly, we reveal that (alpha-PVs), a majority of which infects anogenital mucosa, display the most dramatic reduction in TC dinucleotide content. Computer modeling and reconstruction of ancestral alpha-PV genomes suggest that TC depletion occurred after the alpha-PVs diverged from their most recent common ancestor. In addition, we found that TC depletion in alpha-PVs is greatly affected by protein coding potential. Taken together, our results suggest that PVs replicating in tissues with high APOBEC3 levels may have evolved to evade restriction by selecting for variants that contain reduced APOBEC3 target sites in their genomes.
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http://dx.doi.org/10.1093/ve/vev015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999249PMC
January 2015

Encore: Genetic Association Interaction Network centrality pipeline and application to SLE exome data.

Genet Epidemiol 2013 Sep 5;37(6):614-21. Epub 2013 Jun 5.

Tandy School of Computer Science, University of Tulsa, Tulsa, Oklahoma 74104, USA.

Open source tools are needed to facilitate the construction, analysis, and visualization of gene-gene interaction networks for sequencing data. To address this need, we present Encore, an open source network analysis pipeline for genome-wide association studies and rare variant data. Encore constructs Genetic Association Interaction Networks or epistasis networks using two optional approaches: our previous information-theory method or a generalized linear model approach. Additionally, Encore includes multiple data filtering options, including Random Forest/Random Jungle for main effect enrichment and Evaporative Cooling and Relief-F filters for enrichment of interaction effects. Encore implements SNPrank network centrality for identifying susceptibility hubs (nodes containing a large amount of disease susceptibility information through the combination of multivariate main effects and multiple gene-gene interactions in the network), and it provides appropriate files for interactive visualization of a network using tools from our online Galaxy instance. We implemented these algorithms in C++ using OpenMP for shared-memory parallel analysis on a server or desktop. To demonstrate Encore's utility in analysis of genetic sequencing data, we present an analysis of exome resequencing data from healthy individuals and those with Systemic Lupus Erythematous (SLE). Our results verify the importance of the previously associated SLE genes HLA-DRB and NCF2, and these two genes had the highest gene-gene interaction degrees among the susceptibility hubs. An additional 14 genes previously associated with SLE emerged in our epistasis network model of the exome data, and three novel candidate genes, ST8SIA4, CMTM4, and C2CD4B, were implicated in the model. In summary, we present a comprehensive tool for epistasis network analysis and the first such analysis of exome data from a genetic study of SLE.
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http://dx.doi.org/10.1002/gepi.21739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955726PMC
September 2013

Real-world comparison of CPU and GPU implementations of SNPrank: a network analysis tool for GWAS.

Bioinformatics 2011 Jan 25;27(2):284-5. Epub 2010 Nov 25.

Department of Mathematical and Computer Sciences, University of Tulsa, Tulsa, OK 74104, USA.

Motivation: Bioinformatics researchers have a variety of programming languages and architectures at their disposal, and recent advances in graphics processing unit (GPU) computing have added a promising new option. However, many performance comparisons inflate the actual advantages of GPU technology. In this study, we carry out a realistic performance evaluation of SNPrank, a network centrality algorithm that ranks single nucleotide polymorhisms (SNPs) based on their importance in the context of a phenotype-specific interaction network. Our goal is to identify the best computational engine for the SNPrank web application and to provide a variety of well-tested implementations of SNPrank for Bioinformaticists to integrate into their research.

Results: Using SNP data from the Wellcome Trust Case Control Consortium genome-wide association study of Bipolar Disorder, we compare multiple SNPrank implementations, including Python, Matlab and Java as well as CPU versus GPU implementations. When compared with naïve, single-threaded CPU implementations, the GPU yields a large improvement in the execution time. However, with comparable effort, multi-threaded CPU implementations negate the apparent advantage of GPU implementations.

Availability: The SNPrank code is open source and available at http://insilico.utulsa.edu/snprank.
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http://dx.doi.org/10.1093/bioinformatics/btq638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018810PMC
January 2011