oPOSSUM-3: Advanced Analysis of Regulatory Motif Over-Representation Across Genes or ChIP-Seq Datasets

Kwon, Andrew Tae-Jun; Arenillas, David J.; Hunt, Rebecca Worsley; Wasserman, Wyeth W.

doi:10.1534/g3.112.003202

Cited by 292 publications

(337 citation statements)

References 41 publications

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“…We then used a Python-based bioinformatics analysis to scan these binding regions for the consensus ARE as established in the JASPAR database [27]. We detected 8 putative AREs in the LAMP2 gene (Table S1) and 3 of them showed a relative score higher than 85%, a commonly used threshold for transcription factor binding-site analysis [28,29]. Moreover, the analysis also retrieved already identified AREs in the bona fide target genes of NFE2L2, HMOX1 and SQSTM1/p62 (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

et al. 2018

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Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling mechanisms that control CMA are not fully understood but might involve response to stress conditions including oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) has an impact on CMA modulation. In this work, we identified and validated 2 NFE2L2 binding sequences in the LAMP2 gene and demonstrated in several human and mouse cell types that NFE2L2 deficiency and overexpression was linked to reduced and increased LAMP2A levels, respectively. Accordingly, lysosomal LAMP2A levels were drastically reduced in nfe2l2-knockout hepatocytes, which also displayed a marked decrease in CMA activity. Oxidant challenge with paraquat or hydrogen peroxide, or pharmacological activation of NFE2L2 with sulforaphane or dimethyl fumarate also increased LAMP2A levels and CMA activity. Overall, our study identifies for the first time basal and inducible regulation of LAMP2A, and consequently CMA activity, by NFE2L2.Abbreviations: ACTB: actin, beta, ARE: antioxidant response element; ATG5: autophagy related 5; BACH1: BTB domain and CNC homolog 1; ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; DHE: dihydroethidium; DMF: dimethyl fumarate; ENCODE: Encyclopedia of DNA elements at the University of California, Santa Cruz; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA: glucosylceramidase beta; GFP: green fluorescent protein; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; LAMP1: lysosomal associated membrane protein 1; MAFF: MAF bZIP transcription factor F; MAFK: MAF bZIP transcription factor K; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PQ: paraquat; PI: protease inhibitors; qRT-PCR: quantitative real-time polymerase chain reaction; RNASE: ribonuclease A family member; SFN: sulforaphane; SQSTM1/p62: sequestosome 1; TBP: TATA-box binding protein

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Section: Resultsmentioning

confidence: 99%

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

et al. 2018

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“…Gene ontology (GO) functional annotation analysis was performed either with GeneSpring or using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.7 online tool (15). Single-site analysis to detect over-represented conserved transcription factor binding sites in a set of genes regulated in Parp1 deficiency was performed using the oPOSSUM 3.0 online tool (16). More detailed results of the analyses, including raw and normalized expression values, can be viewed at the National Center for Biotechnology Information Gene Expression Omnibus microarray depository web site (www.ncbi.nlm.nih.gov; GEO accession no.…”

Section: Microarray Analysis Of Colonic Gene Expression Profilementioning

confidence: 99%

Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

Larmonier

Shehab

Laubitz

et al. 2016

Journal of Biological Chemistry

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Poly(ADP-ribose) polymerases (PARPs) synthesize and bind branched polymers of ADP-ribose to acceptor proteins using NAD as a substrate and participate in the control of gene transcription and DNA repair. PARP1, the most abundant isoform, regulates the expression of proinflammatory mediator cytokines, chemokines, and adhesion molecules, and inhibition of PARP1 enzymatic activity reduced or ameliorated autoimmune diseases in several experimental models, including colitis. However, the mechanism(s) underlying the protective effects of PARP1 inhibition in colitis and the cell types in which Parp1 deletion has the most significant impact are unknown. The objective of the current study was to determine the impact of Parp1 deletion on the innate immune response to mucosal injury and on the gut microbiome composition. were protected from dextran-sulfate sodium-induced colitis and that this protection was associated with a dramatic transcriptional reprogramming in the colon. PARP1 deficiency was also associated with a modulation of the colonic microbiota (increases relative abundance of Clostridia clusters IV and XIVa) and a concomitant increase in the frequency of mucosal CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells. The protective effects conferred by Parp1 deletion were lost in Rag2

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“…Therefore, we performed the oPOSSUM program, an enrichment analysis of transcription factor binding motif (34). We identified RELA, SPIB, FOXA2, MZF1_1-4, IRF1, and NF-kB as significantly enriched motifs at the promoter sites of Batf2-regulated genes (Fig.…”

Section: Batf2 Associates With Irf1mentioning

confidence: 99%

Batf2/Irf1 Induces Inflammatory Responses in Classically Activated Macrophages, Lipopolysaccharides, and Mycobacterial Infection

Roy¹,

Guler

Parihar

et al. 2015

The Journal of Immunology

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Basic leucine zipper transcription factor Batf2 is poorly described, whereas Batf and Batf3 have been shown to play essential roles in dendritic cell, T cell, and B cell development and regulation. Batf2 was drastically induced in IFN-γ–activated classical macrophages (M1) compared with unstimulated or IL-4–activated alternative macrophages (M2). Batf2 knockdown experiments from IFN-γ–activated macrophages and subsequent expression profiling demonstrated important roles for regulation of immune responses, inducing inflammatory and host-protective genes Tnf, Ccl5, and Nos2. Mycobacterium tuberculosis (Beijing strain HN878)–infected macrophages further induced Batf2 and augmented host-protective Batf2-dependent genes, particularly in M1, whose mechanism was suggested to be mediated through both TLR2 and TLR4 by LPS and heat-killed HN878 (HKTB) stimulation experiments. Irf1 binding motif was enriched in the promoters of Batf2-regulated genes. Coimmunoprecipitation study demonstrated Batf2 association with Irf1. Furthermore, Irf1 knockdown showed downregulation of IFN-γ– or LPS/HKTB-activated host-protective genes Tnf, Ccl5, Il12b, and Nos2. Conclusively, Batf2 is an activation marker gene for M1 involved in gene regulation of IFN-γ–activated classical macrophages, as well as LPS/HKTB-induced macrophage stimulation, possibly by Batf2/Irf1 gene induction. Taken together, these results underline the role of Batf2/Irf1 in inducing inflammatory responses in M. tuberculosis infection.

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oPOSSUM-3: Advanced Analysis of Regulatory Motif Over-Representation Across Genes or ChIP-Seq Datasets

Cited by 292 publications

References 41 publications

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

Batf2/Irf1 Induces Inflammatory Responses in Classically Activated Macrophages, Lipopolysaccharides, and Mycobacterial Infection

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