Ultraconserved elements in the Olig2 promoter.
Ultraconserved elements in the Olig2 promoter.
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DOI：
10.1371/journal.pone.0003946
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Cohen BA
中科院分区：
文献类型：
--
作者：
Chen CT;Gottlieb DI;Cohen BA
少突胶质细胞是神经系统的特化细胞，其产生围绕神经元轴突的髓鞘。使轴突髓鞘化增加神经传导的速度，并且脱髓鞘有助于神经退行性疾病如多发性硬化症的病理学。少突胶质细胞的分化是由神经管腹侧区域的基本螺旋环螺旋转录因子Olig2的表达在发育早期指定的。因此，了解Olig2的表达是如何控制的，对于阐明少突胶质细胞分化的机制至关重要。需要一种方法来鉴定Olig2侧翼的相邻非编码DNA的长片段中的潜在调控序列。我们根据生物信息学指标的组合确定了Olig2上游的10个潜在调控区域，这些指标包括多个脊椎动物基因组的进化保守性、潜在转录因子结合位点的存在以及超保守元件的存在。我们的一个计算预测包括一个先前确定为Olig2基础启动子的区域，这表明我们的标准代表了已知调控区域的特征。在这项研究中，我们测试了一个候选的调节区域，其调节Olig2基础启动子的能力，发现它抑制未分化的胚胎干细胞的表达。我们确定的调节区修改的方式与我们目前的理解寡突胶质细胞分化过程中的Olig2表达的Olig2基础启动子调控的表达。我们的研究结果支持一种模型，其中Olig2的基本启动子的组成性激活在未分化细胞中被上游抑制元件抑制，直到该抑制在分化过程中被解除。我们的结论是，在这项研究中提出的潜在的调控元件提供了一个很好的起点解开的顺式调控逻辑，管辖Olig2的表达。未来的研究，我们目前的潜在调控元件的功能将有助于揭示在发展过程中的相互作用，管理Olig2的表达。
Oligodendrocytes are specialized cells of the nervous system that produce the myelin sheaths surrounding the axons of neurons. Myelinating the axons increases the speed of nerve conduction and demyelination contributes to the pathology of neurodegenerative diseases such as multiple sclerosis. Oligodendrocyte differentiation is specified early in development by the expression of the basic-helix-loop-helix transcription factor Olig2 in the ventral region of the neural tube. Understanding how Olig2 expression is controlled is therefore essential for elucidating the mechanisms governing oligodendrocyte differentiation. A method is needed to identify potential regulatory sequences in the long stretches of adjacent non-coding DNA that flank Olig2. We identified ten potential regulatory regions upstream of Olig2 based on a combination of bioinformatics metrics that included evolutionary conservation across multiple vertebrate genomes, the presence of potential transcription factor binding sites and the existence of ultraconserved elements. One of our computational predictions includes a region previously identified as the Olig2 basal promoter, suggesting that our criterion represented characteristics of known regulatory regions. In this study, we tested one candidate regulatory region for its ability to modulate the Olig2 basal promoter and found that it represses expression in undifferentiated embryonic stem cells. The regulatory region we identified modifies the expression regulated by the Olig2 basal promoter in a manner consistent with our current understanding of Olig2 expression during oligodendrocyte differentiation. Our results support a model in which constitutive activation of Olig2 by its basal promoter is repressed in undifferentiated cells by upstream repressive elements until that repression is relieved during differentiation. We conclude that the potential regulatory elements presented in this study provide a good starting point for unraveling the cis-regulatory logic that governs Olig2 expression. Future studies of the functionality of the potential regulatory elements we present will help reveal the interactions that govern Olig2 expression during development.
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影响因子：
16.2
作者：
Lu, QR;Yuk, DI;Rowitch, DH
通讯作者：
Rowitch, DH
影响因子：
3
作者：
Bauer, Denis C.;Bailey, Timothy L.
通讯作者：
Bailey, Timothy L.
影响因子：
2.7
作者：
BAIN, G;KITCHENS, D;GOTTLIEB, DI
通讯作者：
GOTTLIEB, DI
影响因子：
6.8
作者：
AKAIKE, H
通讯作者：
AKAIKE, H
DOI：
10.1073/pnas.181340798
发表时间：
2001-09-11
影响因子：
11.1
作者：
Lu, QR;Park, JK;Black, PM
通讯作者：
Black, PM