Binding of high mobility group A proteins to the mammalian genome occurs as a function of AT-content.
Binding of high mobility group A proteins to the mammalian genome occurs as a function of AT-content.
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DOI：
10.1371/journal.pgen.1007102
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发表时间：
2017-12
期刊：
影响因子：
4.5
通讯作者：
Schübeler D
中科院分区：
文献类型：
--
作者：
Colombo DF;Burger L;Baubec T;Schübeler D
基因组定位可以为染色质相关蛋白的潜在功能和募集信号提供信息。高迁移率族（Hmg）蛋白具有与组蛋白相似的大小，其中Hmga 1和Hmga 2在复制正常组织和癌细胞中特别丰富。虽然Hmga蛋白的几个角色已经提出，我们缺乏一个全面的描述，其基因组位置作为一个功能的染色质，DNA序列和功能结构域。在这里，我们报告这样一个特征，在小鼠胚胎干细胞中，我们引入生物素标记的野生型和DNA结合结构域突变体的结构。Hmga蛋白的全基因组分布的比较分析揭示了普遍的结合，一个功能，关键取决于一个功能性的DNA结合结构域，这是由两个Hmga蛋白共享的功能。对这种结合方式有指导意义的潜在队列的评估确定AT丰富度（定义为A或T碱基的高频率）作为局部结合的主要标准。此外，我们表明，其他染色质状态，如那些连接到顺式调节区Hmga结合在干细胞和分化细胞的影响不大。因此，Hmga蛋白优先发现在AT丰富的区域，如组成型异染色质区域，但不存在增强子和启动子，认为在调节单个基因中的作用有限。在这个模型中，我们表明，基因缺失的Hmga蛋白在干细胞中引起有限的转录作用，并结合是保守的神经元祖细胞。总体而言，我们的比较研究描述了Hmga 1和Hmga 2的体内结合方式，确定了蛋白质对全基因组富含AT的DNA的偏好，并反对Hmga在调控区域的建议功能。相反，我们发现广泛的结合与富集在较高的AT含量的区域，而不管染色质修饰的局部变化。我们研究了一组高丰度核蛋白的染色体定位。我们的全基因组的Hmga1和Hmga2的结果揭示了一个独特的结合方式，表明在体内富含A或T碱基的DNA的偏好。重要的是，这种与AT富集序列的优先结合发生在整个基因组中，而与其他局部染色质特征无关。基因组定位和功能丧失实验挑战了Hmga蛋白作为转录调节局部调节剂的观点，而是认为其作为染色质结构组分的作用。
Genomic location can inform on potential function and recruitment signals for chromatin-associated proteins. High mobility group (Hmg) proteins are of similar size as histones with Hmga1 and Hmga2 being particularly abundant in replicating normal tissues and in cancerous cells. While several roles for Hmga proteins have been proposed we lack a comprehensive description of their genomic location as a function of chromatin, DNA sequence and functional domains. Here we report such a characterization in mouse embryonic stem cells in which we introduce biotin-tagged constructs of wild-type and DNA-binding domain mutants. Comparative analysis of the genome-wide distribution of Hmga proteins reveals pervasive binding, a feature that critically depends on a functional DNA-binding domain and which is shared by both Hmga proteins. Assessment of the underlying queues instructive for this binding modality identifies AT richness, defined as high frequency of A or T bases, as the major criterion for local binding. Additionally, we show that other chromatin states such as those linked to cis-regulatory regions have little impact on Hmga binding both in stem and differentiated cells. As a consequence, Hmga proteins are preferentially found at AT-rich regions such as constitutively heterochromatic regions but are absent from enhancers and promoters arguing for a limited role in regulating individual genes. In line with this model, we show that genetic deletion of Hmga proteins in stem cells causes limited transcriptional effects and that binding is conserved in neuronal progenitors. Overall our comparative study describing the in vivo binding modality of Hmga1 and Hmga2 identifies the proteins’ preference for AT-rich DNA genome-wide and argues against a suggested function of Hmga at regulatory regions. Instead we discover pervasive binding with enrichment at regions of higher AT content irrespective of local variation in chromatin modifications. We investigated the chromosomal location of a group of highly abundant nuclear proteins. Our genome-wide results for Hmga1 and Hmga2 reveal a unique binding modality indicating preference for DNA rich in A or T bases in vivo. Importantly this preferential binding to AT-rich sequences occurs throughout the genome irrespectively of other local chromatin features. Genomic location and loss of function experiments challenge the view that Hmga proteins act as local modulators of transcriptional regulation but rather argue for a role as structural components of chromatin.
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影响因子：
14.9
作者：
Burger L;Gaidatzis D;Schübeler D;Stadler MB
通讯作者：
Stadler MB
影响因子：
25
作者：
Bibel, M;Richter, J;Barde, YA
通讯作者：
Barde, YA
DOI：
10.1093/bioinformatics/btv735
发表时间：
2016-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Chiu TP;Comoglio F;Zhou T;Yang L;Paro R;Rohs R
通讯作者：
Rohs R
影响因子：
5.5
作者：
Benecke AG;Eilebrecht S
通讯作者：
Eilebrecht S
影响因子：
7.8
作者：
DISNEY, JE;JOHNSON, KR;REEVES, R
通讯作者：
REEVES, R