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Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related Multiminicore Disease

ABSTRACT: Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related Multiminicore Disease

PROVIDER: PRJNA501797 | ENA |

REPOSITORIES: ENA

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Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related Multiminicore Disease

Project description:Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and mainly caused by mutations in several genes including RYR1, TTN, MYH7 and SELENON4-6. Recessive mutations in either RYR1, encoding a protein involved in calcium homeostasis and excitation–contraction coupling (ECC) or SELENON (previously known as SEPN1), encoding the endoplasmic reticulum glycoprotein selenoprotein N, being the most common identifiable causes of multiminicore disease (MmD). Although recessive SELENON mutations are causative of MmD, the mechanism by which they alter muscle function is still unclear. Here, we extensively investigated skeletal muscle physiological, biochemical and epigenetic modifications in order to understand the pathomechanism of disease. Epigenetic changes including DNA methylation, histone modification and non coding RNA expression are now recognized as playing a major role in the pathophysiology of many human diseases including cancer, Rett, Prader-Willi, Angelmann syndromes, and many more. In the present investigation we found several modifications that are common between patients harbouring recessive RYR1 and SELENON mutations, including depletion of RYR1, ATP2B2, STAC3 and ATP2A1 transcripts, and increased levels of class II HDACs and DNA methyltransferases. Our findings provide insights to design new molecularly based strategies for drug targeting in patients with congenital myopathies characterized by reduced RyR1 protein content.

2019-06-27 | GSE121961 | GEO

Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies.

Project description:Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and caused by pathogenic variants in several genes. Multi-minicore Disease, one of the more common congenital myopathies, is frequently caused by recessive variants in either SELENON, encoding the endoplasmic reticulum glycoprotein selenoprotein N or RYR1, encoding a protein involved in calcium homeostasis and excitation-contraction coupling. The mechanism by which recessive SELENON variants cause Multiminicore disease (MmD) is unclear. Here, we extensively investigated muscle physiological, biochemical and epigenetic modifications, including DNA methylation, histone modification, and noncoding RNA expression, to understand the pathomechanism of MmD. We identified biochemical changes that are common in patients harboring recessive RYR1 and SELENON variants, including depletion of transcripts encoding proteins involved in skeletal muscle calcium homeostasis, increased levels of Class II histone deacetylases (HDACs) and DNA methyltransferases. CpG methylation analysis of genomic DNA of patients with RYR1 and SELENON variants identified >3,500 common aberrantly methylated genes, many of which are involved in calcium signaling. These results provide the proof of concept for the potential use of drugs targeting HDACs and DNA methyltransferases to treat patients with specific forms of congenital myopathies.

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Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia

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Hypermethylated capped selenoprotein mRNAs in mammals

Project description:Mammalian mRNAs are generated by complex and coordinated biogenesis pathways and acquire 5'-end m7G caps that play fundamental roles in processing and translation. Here we show that several selenoprotein mRNAs are not recognized efficiently by translation initiation factor eIF4E because they bear a hypermethylated cap. This cap modification is acquired via a 5’end maturation pathway similar to that of the small nucle(ol)ar RNAs (sn- and snoRNAs). Our findings also establish that the trimethylguanosine synthase 1 (Tgs1) interacts with selenoprotein mRNAs for cap hypermethylation and that assembly chaperones and core proteins devoted to sn- and snoRNP maturation contribute to recruiting Tgs1 to selenoprotein mRNPs. We further demonstrate that the hypermethylated-capped selenoprotein mRNAs localize to the cytoplasm, are associated with polysomes and thus translated. Moreover, we found that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo.

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Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia II

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Hypermethylated capped selenoprotein mRNAs in mammals

Project description:Mammalian mRNAs are generated by complex and coordinated biogenesis pathways and acquire 5'-end m7G caps that play fundamental roles in processing and translation. Here we show that several selenoprotein mRNAs are not recognized efficiently by translation initiation factor eIF4E because they bear a hypermethylated cap. This cap modification is acquired via a 5M-bM-^@M-^Yend maturation pathway similar to that of the small nucle(ol)ar RNAs (sn- and snoRNAs). Our findings also establish that the trimethylguanosine synthase 1 (Tgs1) interacts with selenoprotein mRNAs for cap hypermethylation and that assembly chaperones and core proteins devoted to sn- and snoRNP maturation contribute to recruiting Tgs1 to selenoprotein mRNPs. We further demonstrate that the hypermethylated-capped selenoprotein mRNAs localize to the cytoplasm, are associated with polysomes and thus translated. Moreover, we found that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo. In total 7 samples; 3 control IP (HeLa 1,2 & 9), 2 TGS1-SF IP(C2 & C2b) and 2 TGS1-LF IP(C7 & C7b)

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