Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

Papagianni, Aikaterini; Forés, Marta; Shao, Wanqing; He, Shuonan; Koenecke, Nina; Andreu, María José; Samper, Núria; Paroush, Ze’ev; González-Crespo, Sergio; Zeitlinger, Julia; Jiménez, Gerardo

doi:10.1073/pnas.1713930115

Cited by 38 publications

(50 citation statements)

References 46 publications

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“…During Drosophila development, TLR signaling is initiated when snake cleaves easter, which in turn cleaves spatzle, which then binds to and activates Toll-1 (36). Interestingly, capicua has recently been shown to regulate Toll-1 signaling gene targets (52). Therefore, variations in snake, easter, TLR, and capicua proteins between EGM and AGM populations may alter a TLRcentric signaling pathway that controls wing size.…”

Section: Resultsmentioning

confidence: 99%

Gypsy moth genome provides insights into flight capability and virus–host interactions

Zhang

Cong

Rex

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Since its accidental introduction to Massachusetts in the late 1800s, the European gypsy moth (EGM; Lymantria dispar dispar) has become a major defoliator in North American forests. However, in part because females are flightless, the spread of the EGM across the United States and Canada has been relatively slow over the past 150 years. In contrast, females of the Asian gypsy moth (AGM; Lymantria dispar asiatica) subspecies have fully developed wings and can fly, thereby posing a serious economic threat if populations are established in North America. To explore the genetic determinants of these phenotypic differences, we sequenced and annotated a draft genome of L. dispar and used it to identify genetic variation between EGM and AGM populations. The 865-Mb gypsy moth genome is the largest Lepidoptera genome sequenced to date and encodes ∼13,300 proteins. Gene ontology analyses of EGM and AGM samples revealed divergence between these populations in genes enriched for several gene ontology categories related to muscle adaptation, chemosensory communication, detoxification of food plant foliage, and immunity. These genetic differences likely contribute to variations in flight ability, chemical sensing, and pathogen interactions among EGM and AGM populations. Finally, we use our new genomic and transcriptomic tools to provide insights into genome-wide gene-expression changes of the gypsy moth after viral infection. Characterizing the immunological response of gypsy moths to virus infection may aid in the improvement of virus-based bioinsecticides currently used to control larval populations.

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Section: Resultsmentioning

confidence: 99%

Gypsy moth genome provides insights into flight capability and virus–host interactions

Zhang

Cong

Rex

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…However, our results suggest that in vivo, TF binding to a motif instance is by itself a highly cooperative process that depends on neighboring motifs and syntax. Indeed, in a given cis-regulatory context, lowaffinity motif instances can be an important element of the cis-regulatory code 10,52,117 . The fact that BPNet discovered subtle predictive patterns that are not necessarily strong matches to PWM motif models (e.g.…”

Section: Discussionmentioning

confidence: 99%

Base-resolution models of transcription factor binding reveal soft motif syntax

Avsec

Weilert

Shrikumar

et al. 2019

Preprint

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Genes are regulated through enhancer sequences, in which transcription factor binding motifs and their specific arrangements (syntax) form a cis-regulatory code. To understand the relationship between motif syntax and transcription factor binding, we train a deep learning model that uses DNA sequence to predict base-resolution binding profiles of four pluripotency transcription factors Oct4, Sox2, Nanog, and Klf4. We interpret the model to accurately map hundreds of thousands of motifs in the genome, learn novel motif representations and identify rules by which motifs and syntax influence transcription factor binding. We find that instances of strict motif spacing are largely due to retrotransposons, but that soft motif syntax influences motif interactions at protein and nucleosome range. Most strikingly, Nanog binding is driven by motifs with a strong preference for ~10.5 bp spacings corresponding to helical periodicity. Interpreting deep learning models applied to high-resolution binding data is a powerful and versatile approach to uncover the motifs and syntax of cis-regulatory sequences.

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“…studies also indicated CIC influences Toll/Interleukin-1 signalling. 17 The most well-known CIC downstream target genes include polyomavirus enhancer activator 3 family members genes, ETV1, ETV4 and ETV5 as well as matrix metalloproteinase 9 (MMP9) 18 and MMP24. 19 In the absence of EGFR-ERK signalling, CIC binds to and represses those genes, while activation of the pathway results in inactivation of CIC through phosphorylation induced degradation or relocalisation from the nucleus to the cytoplasm.…”

Section: Neurogeneticsmentioning

confidence: 99%

CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression

et al. 2020

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Background Cerebral folate deficiency (CFD) syndrome is characterised by a low concentration of 5-methyltetrahydrofolate in cerebrospinal fluid, while folate levels in plasma and red blood cells are in the low normal range. Mutations in several folate pathway genes, including FOLR1 (folate receptor alpha, FRα), DHFR (dihydrofolate reductase) and PCFT (proton coupled folate transporter) have been previously identified in patients with CFD.Methods In an effort to identify causal mutations for CFD, we performed whole exome sequencing analysis on eight CFD trios and identified eight de novo mutations in seven trios.Results Notably, we found a de novo stop gain mutation in the capicua (CIC) gene. Using 48 sporadic CFD samples as a validation cohort, we identified three additional rare variants in CIC that are putatively deleterious mutations. Functional analysis indicates that CIC binds to an octameric sequence in the promoter regions of folate transport genes: FOLR1, PCFT and reduced folate carrier (Slc19A1; RFC1). The CIC nonsense variant (p.R353X) downregulated FOLR1 expression in HeLa cells as well as in the induced pluripotent stem cell (iPSCs) derived from the original CFD proband. Folate binding assay demonstrated that the p.R353X variant decreased cellular binding of folic acid in cells.Conclusion This study indicates that CIC loss of function variants can contribute to the genetic aetiology of CFD through regulating FOLR1 expression. Our study described the first mutations in a non-folate pathway gene that can contribute to the aetiology of CFD.

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Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

Cited by 38 publications

References 46 publications

Gypsy moth genome provides insights into flight capability and virus–host interactions

Gypsy moth genome provides insights into flight capability and virus–host interactions

Base-resolution models of transcription factor binding reveal soft motif syntax

CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression

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