Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration
| Autor: | Lauren M. Pachman, Gisela Melcon, Jianhua Xuan, Louis Schiltz, Zuyi Wang, Elena Pegoraro, Po Zhao, Sara T. Winokur, Yitan Zhu, Eric P. Hoffman, Ben Shneiderman, Erynn Gordon, Diana M. Escolar, Corrado Angelini, Marina Bakay, Raul N. Mandler, Yue Wang, Jinwook Seo, Yoram Nevo, Chenguang Fan, Yibin Dong, Vittorio Sartorelli, Yi-Wen Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Transcription
Genetic Nuclear Envelope Biopsy Emerin Thymopoietins Biology MyoD Muscular Dystrophies LMNA medicine Humans Regeneration RNA Messenger Muscular dystrophy Emery–Dreifuss muscular dystrophy Child Muscle Skeletal MyoD Protein Oligonucleotide Array Sequence Analysis Genetics Progeria Models Statistical Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Membrane Proteins Nuclear Proteins medicine.disease Lamin Type A DNA Fingerprinting Muscular Dystrophy Emery-Dreifuss Mutation Nuclear lamina Neurology (clinical) Lamin Protein Binding |
| Popis: | Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell-specific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBEI). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, Nap1L1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells. |
| Databáze: | OpenAIRE |
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