Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration
Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration
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DOI：
10.1093/brain/awl023
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发表时间：
2006-04-01
期刊：
影响因子：
14.5
通讯作者：
Hoffman, EP
中科院分区：
文献类型：
--
作者：
Bakay, M;Wang, ZY;Hoffman, EP
纤层蛋白A/C （LMNA）突变引起广泛的人类疾病，包括早衰症、脂肪营养不良症、神经病变和常染色体显性埃默里-德莱弗斯肌营养不良症（EDMD）。EDMD也是由emerin的x连锁隐性功能丧失突变引起的，emerin是内核层的另一种直接与LMNA相互作用的成分。LMNA和emerin突变的疾病发病机制的一个模型是终末分化细胞中mRNA转录组的细胞特异性扰动。为了验证该模型，我们研究了来自13个诊断组（125个U133A， 125个U133B微阵列）的125个人体肌肉活检，包括LMNA和emerin突变的EDMD患者。使用VISDA （Visual and Statistical Data Analyzer）算法对聚类层次进行统计建模，得到表型分类树。诊断树的验证包括U133A和U133B阵列的排列，并使用两种探针集算法（MAS5.0和MBEI）。这表明两种核膜缺陷（EDMD LMNA, EDMD emerin）是高度相关的疾病，也与筋膜肩胛肱肌营养不良（FSHD）有关。FSHD最近被假设与染色质与核膜的异常相互作用有关。为了鉴定EDMD的疾病特异性转录本，我们采用了留一（LOO）交叉验证方法，使用LMNA患者肌肉作为测试数据集，并在LMNA和emerin患者肌肉中进行逆转录聚合酶链反应（RT-PCR）验证。在肌肉再生过程中，高比例的排名和验证的转录本是涉及Rb1和MyoD的相同转录调控途径的组成部分（CRI-1， CREBBP, Nap1L1, ECREBBP/p300），其中每个转录本在EDMD中都被特异性上调。使用肌肉再生时间序列（27个时间点），我们开发了LMNA和emerin突变的下游后果的转录模型。我们提出，EDMD中核膜与Rb和MyoD之间的关键相互作用在成肌细胞退出细胞周期时失效，导致磷酸化和乙酰化步骤不协调。我们的数据与导致分化细胞中转录组不稳定的核层成分突变一致。
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.