Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration

Marina Bakay, Zuyi Wang, Gisela Melcon, Louis Schiltz, Jianhua Xuan, Po Zhao, Vittorio Sartorelli, Jinwook Seo, Elena Pegoraro, Corrado Angelini, Ben Shneiderman, Diana Escolar, Yi Wen Chen, Sara T. Winokur, Lauren M. Pachman, Chenguang Fan, Raul Mandler, Yoram Nevo, Erynn Gordon, Yitan ZhuYibin Dong, Yue Wang, Eric P. Hoffman

Research output: Contribution to journalArticle

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 MBE1). 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, NapIL1, 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.

Original languageEnglish
Pages (from-to)996-1013
Number of pages18
JournalBrain
Volume129
Issue number4
DOIs
Publication statusPublished - Apr 2006

Fingerprint

Emery-Dreifuss Muscular Dystrophy
Lamin Type A
Nuclear Envelope
Dermatoglyphics
Regeneration
Muscles
Mutation
Nuclear Lamina
Muscular Dystrophies
Transcriptome
Progeria
Lipodystrophy
Myoblasts
Acetylation
Reverse Transcription
Chromatin
emerin
Cell Cycle
Phosphorylation
Biopsy

Keywords

  • Emerin
  • Emery-Dreifuss muscular dystrophy
  • Lamin A/C
  • Skeletal muscle

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Bakay, M., Wang, Z., Melcon, G., Schiltz, L., Xuan, J., Zhao, P., ... Hoffman, E. P. (2006). Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain, 129(4), 996-1013. https://doi.org/10.1093/brain/awl023

Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. / Bakay, Marina; Wang, Zuyi; Melcon, Gisela; Schiltz, Louis; Xuan, Jianhua; Zhao, Po; Sartorelli, Vittorio; Seo, Jinwook; Pegoraro, Elena; Angelini, Corrado; Shneiderman, Ben; Escolar, Diana; Chen, Yi Wen; Winokur, Sara T.; Pachman, Lauren M.; Fan, Chenguang; Mandler, Raul; Nevo, Yoram; Gordon, Erynn; Zhu, Yitan; Dong, Yibin; Wang, Yue; Hoffman, Eric P.

In: Brain, Vol. 129, No. 4, 04.2006, p. 996-1013.

Research output: Contribution to journalArticle

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, YW, Winokur, ST, Pachman, LM, Fan, C, Mandler, R, Nevo, Y, Gordon, E, Zhu, Y, Dong, Y, Wang, Y & Hoffman, EP 2006, 'Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration', Brain, vol. 129, no. 4, pp. 996-1013. https://doi.org/10.1093/brain/awl023
Bakay, Marina ; Wang, Zuyi ; Melcon, Gisela ; Schiltz, Louis ; Xuan, Jianhua ; Zhao, Po ; Sartorelli, Vittorio ; Seo, Jinwook ; Pegoraro, Elena ; Angelini, Corrado ; Shneiderman, Ben ; Escolar, Diana ; Chen, Yi Wen ; Winokur, Sara T. ; Pachman, Lauren M. ; Fan, Chenguang ; Mandler, Raul ; Nevo, Yoram ; Gordon, Erynn ; Zhu, Yitan ; Dong, Yibin ; Wang, Yue ; Hoffman, Eric P. / Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. In: Brain. 2006 ; Vol. 129, No. 4. pp. 996-1013.
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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 MBE1). 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, NapIL1, 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.",
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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.

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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 MBE1). 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, NapIL1, 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.

AB - 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 MBE1). 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, NapIL1, 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.

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KW - Emery-Dreifuss muscular dystrophy

KW - Lamin A/C

KW - Skeletal muscle

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