Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

Johnson, Michael R.; Behmoaras, Jacques; Bottolo, Leonardo; Krishnan, Michelle L.; Pernhorst, Katharina; Santoscoy, Paola L. Meza; Rossetti, Tiziana; Speed, Doug; Srivastava, Prashant K.; Chadeau‐Hyam, Marc; Hajji, Nabil; Dabrowska, Aleksandra; Rotival, Maxime; Razzaghi, Banafsheh; Kovač, Stjepana; Wanisch, Klaus; Grillo, Federico W.; Slaviero, Anna; Langley, Sarah R.; Shkura, Kirill; Roncon, Paolo; De, Tisham; Mattheisen, Manuel; Niehusmann, Pitt; O’Brien, Terence J.; Petrovski, Slavé; Lehe, Marec von; Hoffmann, Per; Eriksson, Johan G.; Coffey, Alison J.; Cichon, Sven; Walker, Matthew C.; Simonato, Michele; Danis, Bénédicte; Mazzuferi, Manuela; Foerch, Patrik; Schoch, Susanne; Paola, Vincenzo De; Kamiński, Rafał M.; Cunliffe, Vincent T.; Becker, Albert; Petretto, Enrico

doi:10.1038/ncomms7031

Cited by 160 publications

(132 citation statements)

References 56 publications

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“…Our results indicate that a different transcriptional response is present in the case of clinical depression (Table S2 and Dataset S4), consistent also with results for epilepsy derived considering the differentially expressed genes in hippocampal samples from five patients with mesial temporal lobe epilepsy with hippocampal sclerosis (55). In that study, 518 genes were found to be differentially expressed between the subjects.…”

Section: Discussionsupporting

confidence: 77%

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

Ciryam

Kundra

Freer

et al. 2016

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

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It is well-established that widespread transcriptional changes accompany the onset and progression of Alzheimer’s disease. Because of the multifactorial nature of this neurodegenerative disorder and its complex relationship with aging, however, it remains unclear whether such changes are the result of nonspecific dysregulation and multisystem failure or instead are part of a coordinated response to cellular dysfunction. To address this problem in a systematic manner, we performed a meta-analysis of about 1,600 microarrays from human central nervous system tissues to identify transcriptional changes upon aging and as a result of Alzheimer’s disease. Our strategy to discover a transcriptional signature of Alzheimer’s disease revealed a set of down-regulated genes that encode proteins metastable to aggregation. Using this approach, we identified a small number of biochemical pathways, notably oxidative phosphorylation, enriched in proteins vulnerable to aggregation in control brains and encoded by genes down-regulated in Alzheimer’s disease. These results suggest that the down-regulation of a metastable subproteome may help mitigate aberrant protein aggregation when protein homeostasis becomes compromised in Alzheimer’s disease.

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Section: Discussionsupporting

confidence: 77%

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

Ciryam

Kundra

Freer

et al. 2016

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

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“…1A). High-throughput sequencing of mRNA (RNA-seq) was carried out in whole hippocampus samples from 100 epileptic and 100 control littermate mice (same age) as previously described (Johnson et al 2015a). All mice underwent continuous video monitoring for 14 consecutive days beginning 28 days following pilocarpineinduced status epilepticus to document the occurrence and frequency of spontaneous behavioral epileptic seizures, as previously described (Mazzuferi et al 2012).…”

Section: Methodsmentioning

confidence: 99%

“…To integrate these data across their variable sources and coverage, we assumed each gene has 100% of its consensus CDS covered across all trios, as previously described (Johnson et al 2015a). For each disorder, we included single nucleotide variant (nonsynonymous) DNMs considering all missense, nonsense, and splice-site SNV mutations.…”

Section: Assessing Enrichment In Rare De Novo Mutations In Neurodevelmentioning

confidence: 99%

Genome-wide analysis of differential RNA editing in epilepsy

et al. 2017

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The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine-temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including "neuron projection" and "seizures." Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures.

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“…What’s more, Sesn3 was found to be the transcriptional module that encoded proconvulsive cytokines and Toll-like receptor signaling genes in macrophages, microglia and neurons. The knockdown of Sesn3 in zebrafish attenuated chemically induced behavioral seizures [62]. This study suggested the potential pro-epilepsy effect of Sesn3 and further indicated the different function of Sesns in different central nervous diseases.…”

Section: Sesns In the Nervous Systemmentioning

confidence: 99%

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Wang

Liu

et al. 2017

Cell Physiol Biochem

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Sestrins (Sesns) have been identified as a family of highly conserved stress-inducible proteins that are strongly up-regulated by various stresses, including DNA damage, oxidative stress, and hypoxia. The Sesns play protective roles in most physiological and pathological conditions mainly through the regulation of oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and metabolic homeostasis. In this review, we discussed the possible regulators of Sesns expression, such as p53, forkhead box O, nuclear factor erythroid 2 like 2 (Nrf2), NH (2)-terminal kinase (JNK)/c-Jun pathway and hypoxia-inducible factor-1α (Hif-1α), and the downstream pathways regulated by the Sesns including AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, mitogen-activated protein kinases (MAPKs) signaling, Nrf2 signaling, NADPH oxidase signaling and transforming growth factor β (TGF-β) signaling in heart diseases, lung diseases, gastrointestinal tract diseases, liver and metabolism diseases, neurological diseases, kidney diseases and immunological diseases. This review aims to provide a comprehensive understanding the protective effects of Sesns.

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Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

Cited by 160 publications

References 56 publications

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

Genome-wide analysis of differential RNA editing in epilepsy

Recent Insights into the Biological Functions of Sestrins in Health and Disease

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