Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency.
Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency.
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DOI：
10.1038/nn.2172
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发表时间：
2008-09
影响因子：
25
通讯作者：
Casaccia-Bonnefil, Patrizia
中科院分区：
文献类型：
--
作者：
Shen, Siming;Sandoval, Juan;Swiss, Victoria A.;Li, Jiadong;Dupree, Jeff;Franklin, Robin J. M.;Casaccia-Bonnefil, Patrizia
髓鞘再生的效率随着年龄的增长而降低，但导致这种下降的分子机制仍然只有部分了解。在这项研究中，我们表明，髓鞘再生的基因表达的年龄依赖性表观遗传控制。在脱髓鞘的年轻大脑中，新的髓鞘合成之前，少突胶质细胞分化抑制剂和神经干细胞标志物的下调，这与组蛋白脱乙酰酶（HDAC）的启动子区域的招聘。在脱髓鞘的老年大脑中，HDAC募集效率低下，这使得转录抑制剂积累，并阻止了随后的髓鞘基因表达激增。缺陷的髓鞘再生可以在体内重演，在cuprizone治疗期间接受药理学HDAC抑制剂的全身给药的小鼠中，并且与体外结果一致，该结果显示在沉默特定HDAC同种型后少突胶质细胞祖细胞的分化缺陷。因此，我们认为，少突胶质细胞分化程序的低效表观遗传调制有助于髓鞘再生效率的年龄依赖性下降。
The efficiency of remyelination decreases with age, but the molecular mechanisms responsible for this decline remain only partially understood. In this study, we show that remyelination is regulated by age-dependent epigenetic control of gene expression. In demyelinated young brains, new myelin synthesis is preceded by downregulation of oligodendrocyte differentiation inhibitors and neural stem cell markers, and this is associated with recruitment of histone deacetylases (HDACs) to promoter regions. In demyelinated old brains, HDAC recruitment is inefficient, and this allows the accumulation of transcriptional inhibitors and prevents the subsequent surge in myelin gene expression. Defective remyelination can be recapitulated in vivo in mice receiving systemic administration of pharmacological HDAC inhibitors during cuprizone treatment and is consistent with in vitro results showing defective differentiation of oligodendrocyte progenitors after silencing specific HDAC isoforms. Thus, we suggest that inefficient epigenetic modulation of the oligodendrocyte differentiation program contributes to the age-dependent decline in remyelination efficiency.
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影响因子：
6.4
作者：
Albert, Monika;Antel, Jack;Stadelmann, Christine
通讯作者：
Stadelmann, Christine
影响因子：
3.5
作者：
Hinks, GL;Franklin, RJM
通讯作者：
Franklin, RJM
影响因子：
158.5
作者：
Chang, A;Tourtellotte, WW;Trapp, BD
通讯作者：
Trapp, BD
DOI：
10.1073/pnas.0407836102
发表时间：
2005-02-15
影响因子：
11.1
作者：
Le, N;Nagarajan, R;Milbrandt, J
通讯作者：
Milbrandt, J
DOI：
10.1073/pnas.0407643101
发表时间：
2004-11-23
影响因子：
11.1
作者：
Hsieh, J;Nakashima, K;Gage, FH
通讯作者：
Gage, FH