基于对转录因子结合亲缘关系分析的哺乳动物增强剂的全基因组预测
Outi Hallikas1, Kimmo Palin, Natalia Sinjushina
1Molecular and Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Finland.
Cell
|January 18, 2006
概括
研究人员绘制了转录因子结合特异性,并开发了一种工具来识别基因增强剂. 这促进了对人类基因表达及其在发育和癌症中的作用的理解.
科学领域:
- 分子生物学分子生物学
- 基因组学就是基因组学.
- 生物信息学是一种生物信息学.
背景情况:
- 人类基因表达受到转录因子 (TF) 和增强元件的调节.
- 了解TF结合的组合代码对于破译基因调节至关重要.
- 诸如 (Hh),Wnt和Ras/MAPK之类的关键信号通路涉及特定的TF.
研究的目的:
- 为了确定GLI1-3,Tcf4和c-Ets1 TFs的DNA结合特异性.
- 开发一种计算工具 (增强元件定位器 - - EEL) 用于在基因组规模上识别哺乳动物增强元件.
- 调查已识别的增强剂在调节参与发育和疾病的基因中的作用.
主要方法:
- 使用一种新的高通量方法来确定TF DNA的结合特异性.
- 开发和使用了增强元件定位器 (EEL) 计算工具.
- 使用转基因小鼠胚胎验证了预测.
主要成果:
- 确定了GLI1-3,TCF4和c-Ets1的DNA结合特异性.
- EEL成功识别了Hh和Wnt目标基因,并预测了激活的TFs.
- 在小鼠的c-Myc和N-Myc基因中发现了组织特异性增强剂,在体内验证.
结论:
- 这项研究阐明了控制人类基因表达的"第二个遗传密码".
- 开发的EEL工具可以大规模识别受路径调节的增强剂.
- 这些发现对理解瘤中的器官特异生长和瘤基因特异性有重大影响.
相关概念视频
02:16Transcription Factors
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
01:49Conserved Binding Sites
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
02:36RNA Polymerase II Accessory Proteins
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
02:42Eukaryotic Transcription Activators
Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These domains are...
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These domains are...
02:23Master Transcription Regulators
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
01:30General Transcription Factors
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...