Significance
Our results demonstrate that connexin 43 hemichannels are the conduits for amyotrophic lateral sclerosis (ALS) astrocyte-mediated motor neuron toxicity and disease spread, acting as a common mechanism that can target both familial ALS and sporadic ALS populations. Furthermore, our present work provides proof of principle that tonabersat, as a drug already studied in clinical trials for other indications, could serve as a potential ALS therapeutic.
Formation of a zygote is coupled with extensive epigenetic reprogramming to enable appropriate inheritance of histone methylation and prevent developmental delays. In C. elegans, this reprogramming is mediated by the H3K4me2 demethylase, SPR-5, and the H3K9 methyltransferase, MET-2. In contrast, the H3K36 methyltransferase, MES-4, maintains H3K36me2/3 at germline genes between generations to facilitate re-establishment of the germline. To determine whether the MES-4 germline inheritance pathway antagonizes spr-5; met-2 reprogramming, we examined the interaction between these two pathways. We find that the developmental delay of spr-5; met-2 mutant progeny is associated with ectopic H3K36me3 and the ectopic expression of MES-4 targeted germline genes in somatic tissues. Furthermore, the developmental delay is dependent upon MES-4 and the H3K4 methyltransferase, SET-2. We propose that MES-4 prevents critical germline genes from being repressed by antagonizing maternal spr-5; met-2 reprogramming. Thus, the balance of inherited histone modifications is necessary to distinguish germline versus soma and prevent developmental delay.
1In C. elegans, the H3K36 methyltransferase, MES-4, helps establish germ cell fate by 2 maintaining H3K36me2/3 at germline genes between generations. Previously, we showed 3 that the H3K4me2 demethylase, SPR-5, and the H3K9 methyltransferase, 4 reprogram histone methylation at fertilization to prevent the ectopic expression of 5 germline genes in somatic tissues. Together, this indicates that SPR-5 and MET-2 maternal 6reprogramming may antagonize MES-4 to establish germline versus soma. Here, we show 7 that spr-5; met-2 mutant progeny have a severe developmental delay that is associated with 8 the ectopic maintenance of H3K36me2/3 at MES-4 targeted germline genes in somatic 9 tissues, and the ectopic expression of these genes. We further show that the developmental 10 delay and the ectopic expression are dependent upon MES-4. Thus, we propose that SPR-5, 11MET-2, and MES-4 balance inherited histone methylation to establish germline versus 12 soma. Without this balance, the inappropriate transcription of germline genes in somatic 13 tissues causes developmental delay. 14 15
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