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	Marta Barrachina, Jesús Moreno, Salvador Juvés, Dolores Moreno, Montse Olivé, Isidre Ferrer
Journal	The American journal of pathology (Am J Pathol) Vol. 171 Issue 4 Pg. 1312-23 (Oct 2007) ISSN: 0002-9440 [Print] United States
PMID	17823282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Connectin Cytoskeletal Proteins Intermediate Filament Proteins MYOT protein, human Microfilament Proteins Muscle Proteins Nerve Tissue Proteins RE1-silencing transcription factor RNA, Messenger Repressor Proteins Synaptophysin Synaptosomal-Associated Protein 25 Transcription Factors UCHL1 protein, human alpha-internexin Ubiquitin Thiolesterase
Topics	Aged Aged, 80 and over Connectin Cytoskeletal Proteins (analysis) Female Gene Expression Regulation HeLa Cells Humans Intermediate Filament Proteins (genetics, metabolism) Male Microfilament Proteins Middle Aged Muscle Fibers, Skeletal (chemistry, metabolism, pathology) Muscle Proteins (analysis) Muscular Diseases (genetics, pathology) Nerve Tissue Proteins (genetics, metabolism) Promoter Regions, Genetic RNA, Messenger (analysis, metabolism) Repressor Proteins (antagonists & inhibitors, genetics, metabolism) Synaptophysin (genetics, metabolism) Synaptosomal-Associated Protein 25 (genetics, metabolism) Transcription Factors (antagonists & inhibitors, genetics, metabolism) Transfection Ubiquitin Thiolesterase (analysis, genetics, metabolism) Up-Regulation

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