Epithelium specific ETS transcription factor, ESE-3, of Protobothrops flavoviridis snake venom gland transactivates the promoters of venom phospholipase A2 isozyme genes

Nakamura, Hitomi; Murakami, Tatsuo; Hattori, Satoshi; Sakaki, Yoshiyuki; Ohkuri, Takatoshi; Chijiwa, Takahito; Ohno, Motonori; Oda-Ueda, Naoko

doi:10.1016/j.toxicon.2014.10.001

Cited by 8 publications

(4 citation statements)

References 29 publications

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“…2 A; Luna et al 2009 ). An additional SE-associated candidate TF (EHF) was previously suggested to play a role in regulating venom PLA 2 genes in Protobothrops ( Nakamura et al 2014 ). Other candidate TFs have been identified as potential regulators of VGs in separate genomic studies, including FOX-family TFs, GRHL1, NFIA and NFIB, XBP1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5A). A TFBS for EHF, which was previously implicated in PLA 2 regulation (Nakamura et al 2014), is putatively bound in a single PLA 2 vPER inferred to target both of the highly expressed PLA 2 genes (PLA 2 A1 and PLA 2 B1) (Fig. 5A).…”

Section: Patterns Of Enhancer Tfbss and Links To Erk And Upr Signalingmentioning

confidence: 99%

“…To date, a small number of studies have identified several transcription factors (TFs) and signaling pathways that may play a regulatory role in at least some species and some VG families, although no studies have identified the scope of the regulatory system that broadly regulates snake venom expression, or the evolutionary origins of this regulatory system ( Yamanouye et al 2000 ; Kerchove et al 2004 , 2008 ; Hargreaves et al 2014b ; Junqueira-de-Azevedo et al 2015 ; Zancolli and Casewell 2020 ; Margres et al 2021 ). These studies identified a set of TFs, including AP-1, NF-kB, and FOX-, NF1-, and GRHL-family members, for which identifiable binding sites occur in the promoters of various VGs ( Luna et al 2009 ; Nakamura et al 2014 ; Schield et al 2019 ; Margres et al 2021 ). Other studies have implicated the high-level regulatory involvement of alpha- and beta-adrenergic receptors and signaling through the ERK/MAPK pathway in initiating the venom production cascade ( Yamanouye et al 2000 ; Kerchove et al 2008 ); however, subsequent studies have performed little to investigate putative venom TFs in light of higher-level regulatory networks.…”

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confidence: 99%

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Snake venom gene expression is coordinated by novel regulatory architecture and the integration of multiple co-opted vertebrate pathways

et al. 2022

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Understanding how regulatory mechanisms evolve is critical for understanding the processes that give rise to novel phenotypes. Snake venom systems represent a valuable and tractable model for testing hypotheses related to the evolution of novel regulatory networks, yet the regulatory mechanisms underlying venom production remain poorly understood. Here, we use functional genomics approaches to investigate venom regulatory architecture in the prairie rattlesnake and identify cis-regulatory sequences (enhancers and promoters), trans-regulatory transcription factors, and integrated signaling cascades involved in the regulation of snake venom genes. We find evidence that two conserved vertebrate pathways, the extracellular signal-regulated kinase and unfolded protein response pathways, were co-opted to regulate snake venom. In one large venom gene family (snake venom serine proteases), this co-option was likely facilitated by the activity of transposable elements. Patterns of snake venom gene enhancer conservation, in some cases spanning 50 million yr of lineage divergence, highlight early origins and subsequent lineage-specific adaptations that have accompanied the evolution of venom regulatory architecture. We also identify features of chromatin structure involved in venom regulation, including topologically associated domains and CTCF loops that underscore the potential importance of novel chromatin structure to coevolve when duplicated genes evolve new regulatory control. Our findings provide a model for understanding how novel regulatory systems may evolve through a combination of genomic processes, including tandem duplication of genes and regulatory sequences, cis-regulatory sequence seeding by transposable elements, and diverse transcriptional regulatory proteins controlled by a co-opted regulatory cascade.

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Section: Resultsmentioning

confidence: 99%

Section: Patterns Of Enhancer Tfbss and Links To Erk And Upr Signalingmentioning

confidence: 99%

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confidence: 99%

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Snake venom gene expression is coordinated by novel regulatory architecture and the integration of multiple co-opted vertebrate pathways

et al. 2022

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“…These studies have identified cis -regulatory elements (CRE) that regulate the expression of genes encoding 3FTx and group I PLA 2 expression in the Javan Spitting Cobra ( Naja sputatrix ) (Jeyaseelan et al 2000; Ma et al 2001; Ma et al 2002), the pseutarin C catalytic subunit in the Eastern Brown Snake ( Pseudonaja textilis ) (Kwong et al 2009), and silencer AG-rich motifs in the first intron of the pseutarin C catalytic subunit gene (Han et al 2016). Investigations of viperids have found α1− and β−adrenoceptor signaling as a mechanism activating transcription factors (TFs) NF-kB and AP-1 to initiate toxin synthesis in the Jararaca ( Bothrops jararaca ) (Yamanouye et al 1997; Luna et al 2009), tissue-specific TF ESE-3 upregulated group II PLA 2 s genes in the Habu ( Protobothrops flavoviridis ) (Nakamura et al 2014), and CREs for binding GRHL-and NFI-family TFs were enriched within SVMP, SVSP, and group II PLA 2 gene promoters in the Prairie and Tiger rattlesnakes ( Crotalus viridis and C. tigris , respectively) (Schield et al 2019; Margres et al 2021; Perry et al 2022), in addition to co-opted TFs from the Unfolded Protein Response (UPR) pathway (Perry et al 2022). Current evidence suggests that for the viperids C. viridis and C. tigris, toxin gene expression is regulated by chromatin structure, TFs, and gene methylation levels (Schield et al 2019; Margres et al 2021).…”

Section: Introductionmentioning

confidence: 99%

Distinct regulatory networks control toxin gene expression in elapid and viperid snakes

Modahl

Han

Thiel

et al. 2023

Preprint

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Venom systems are ideal models to study genetic regulatory mechanisms that underpin evolutionary novelty. Snake venom glands are thought to share a common origin, but there are major distinctions between venom toxins from the medically significant snake families Elapidae and Viperidae, and toxin gene regulation in elapids is largely unexplored. Here, we used high-throughput RNA-sequencing to profile gene expression and microRNAs between active (milked) and resting (unmilked) venom glands in an elapid (Eastern Brown Snake, Pseudonaja textilis), in addition to comparative genomics, to identify cis- and trans- acting regulation of venom production in an elapid in comparison to viperids (Crotalus viridis and C. tigris). Although there is conservation in high-level mechanistic pathways regulating venom production, there are histone methylation, transcription factor, and microRNA regulatory differences between these two snake families. Histone methyltransferases (KMT2A, KMT2C and KMT2D) and transcription factor (TF) specificity protein 1 (Sp1) were highly upregulated in the milked elapid venom gland, whereas nuclear factor I (NFI) TFs were upregulated after viperid venom milking. Sp1 and NFI cis-regulatory elements were common to toxin gene promoter regions, but many unique elements were also present between elapid and viperid toxins. microRNA profiles were distinctive between milked and unmilked venom glands for both snake families, and microRNAs were predicted to target different toxin transcripts. Our comparative transcriptomic and genomic analyses between toxin genes and isoforms in elapid and viperid snakes suggests independent toxin evolution between these two snake families, demonstrating multiple toxin genes and regulatory mechanisms converged to underpin a highly venomous phenotype.

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Snake Venom Phospholipase A2: Evolution and Diversity

Tsai

2016

Venom Genomics and Proteomics

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Epithelium specific ETS transcription factor, ESE-3, of Protobothrops flavoviridis snake venom gland transactivates the promoters of venom phospholipase A2 isozyme genes

Cited by 8 publications

References 29 publications

Snake venom gene expression is coordinated by novel regulatory architecture and the integration of multiple co-opted vertebrate pathways

Snake venom gene expression is coordinated by novel regulatory architecture and the integration of multiple co-opted vertebrate pathways

Distinct regulatory networks control toxin gene expression in elapid and viperid snakes

Snake Venom Phospholipase A2: Evolution and Diversity

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