title: Target genes of neuron-restrictive silencer factor are abnormally up-regulated in human myotilinopathy.
abstract: Myotilinopathy is a subgroup of myofibrillar myopathies caused by mutations in the myotilin gene in which there is aggregation of abnormal cytoskeletal proteins and ubiquitin. We report here on the accumulation of neuron-related proteins such as ubiquitin carboxy-terminal hydrolase L1 (UCHL1), synaptosomal-associated protein 25, synaptophysin, and alpha-internexin in aberrant protein aggregates in myotilinopathy. We have determined that the neuron-restrictive silencer factor (NRSF)/RE1 silencing transcription factor (REST), a transcription factor expressed in non-neuronal tissues repressing the expression of several neuronal genes, is reduced in myotilinopathies. Moreover, NRSF transfection reduces UCHL1, synaptosomal-associated protein 25, synaptophysin, and alpha-internexin mRNA levels in DMS53 cells, whereas short interferring NRSF transfection increases UCHL1 and synaptophysin mRNA levels in U87-MG cells. Chromatin immunoprecipitation assays have shown that NRSF interacts with the UCHL1 promoter in U87-MG and HeLa cells. In silico analysis of the UCHL1 gene promoter sequence using the MatInspector software has predicted three potential neuron-restrictive silencer elements (NRSEs): NRSE1 located in the complementary DNA chain and NRSE2 and NRSE3 in intron 1, in the coding and complementary chains, respectively. Together, these findings show, for the first time, abnormal regulation of NRSF/REST as a mechanism associated with the aberrant expression of selected neuron-related proteins, which in turn accumulate in abnormal protein aggregates, in myotilinopathy.
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, carrer Feixa Llarga sn, 08907 L'Hospitalet de Llobregat, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Barrachina
authors.forename: Jesús
authors.initials: J
authors.lastname: Moreno
authors.forename: Salvador
authors.initials: S
authors.lastname: Juvés
authors.forename: Dolores
authors.initials: D
authors.lastname: Moreno
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D064211:Connectin; D003598:Cytoskeletal Proteins / Q000032:analysis; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000032:analysis; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000099229:RE1-Silencing Transcription Factor