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Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration.
Brain. 2006 Apr; 129(Pt 4):996-1013.B

Abstract

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.

Authors+Show Affiliations

Research Center for Genetic Medicine, Children's National Medical Center, Washington DC 20010, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16478798

Citation

Bakay, Marina, et al. "Nuclear Envelope Dystrophies Show a Transcriptional Fingerprint Suggesting Disruption of Rb-MyoD Pathways in Muscle Regeneration." Brain : a Journal of Neurology, vol. 129, no. Pt 4, 2006, pp. 996-1013.
Bakay M, Wang Z, Melcon G, et al. Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain. 2006;129(Pt 4):996-1013.
Bakay, M., Wang, Z., Melcon, G., Schiltz, L., Xuan, J., Zhao, P., Sartorelli, V., Seo, J., Pegoraro, E., Angelini, C., Shneiderman, B., Escolar, D., Chen, Y. W., Winokur, S. T., Pachman, L. M., Fan, C., Mandler, R., Nevo, Y., Gordon, E., ... Hoffman, E. P. (2006). Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain : a Journal of Neurology, 129(Pt 4), 996-1013.
Bakay M, et al. Nuclear Envelope Dystrophies Show a Transcriptional Fingerprint Suggesting Disruption of Rb-MyoD Pathways in Muscle Regeneration. Brain. 2006;129(Pt 4):996-1013. PubMed PMID: 16478798.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. AU - Bakay,Marina, AU - Wang,Zuyi, AU - Melcon,Gisela, AU - Schiltz,Louis, AU - Xuan,Jianhua, AU - Zhao,Po, AU - Sartorelli,Vittorio, AU - Seo,Jinwook, AU - Pegoraro,Elena, AU - Angelini,Corrado, AU - Shneiderman,Ben, AU - Escolar,Diana, AU - Chen,Yi-Wen, AU - Winokur,Sara T, AU - Pachman,Lauren M, AU - Fan,Chenguang, AU - Mandler,Raul, AU - Nevo,Yoram, AU - Gordon,Erynn, AU - Zhu,Yitan, AU - Dong,Yibin, AU - Wang,Yue, AU - Hoffman,Eric P, Y1 - 2006/02/14/ PY - 2006/2/16/pubmed PY - 2006/4/18/medline PY - 2006/2/16/entrez SP - 996 EP - 1013 JF - Brain : a journal of neurology JO - Brain VL - 129 IS - Pt 4 N2 - 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. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/16478798/Nuclear_envelope_dystrophies_show_a_transcriptional_fingerprint_suggesting_disruption_of_Rb_MyoD_pathways_in_muscle_regeneration_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awl023 DB - PRIME DP - Unbound Medicine ER -