在雌激素受体转录程序中的增强剂序列的机械分析
Shayan Tabe-Bordbar1, You Jin Song2, Bryan J Lunt1
1Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Communications biology
|June 11, 2024
概括
研究人员开发了模型,以了解增强剂的DNA序列如何控制乳腺癌中的基因活性. 这些模型可以预测增强器的功能,并识别与疾病相关的遗传变异.
科学领域:
- 基因组学就是基因组学.
- 分子生物学分子生物学
- 生物信息学是一种生物信息学.
背景情况:
- 雌激素受体α (ERα) 是乳腺发育中的关键转录因子,其失调与乳腺癌有关.
- 了解增强剂,调节性DNA元素如何在ERα驱动的途径中起作用,对于癌症研究至关重要.
- 增强剂RNAs (eRNAs) 从活性增强剂转录,作为其功能的潜在标记物.
研究的目的:
- 开发基于序列的模型,可以区分转录和非转录的ERα结合增强剂.
- 获得关于特定转录因子 (TF) 在ERα介导的基因调节中的作用的机制性见解.
- 预测TF增强剂的调控关系,构建与乳腺癌相关的基因调控网络.
主要方法:
- 使用定量,机理意识模型分析数千种与ERα结合的增强剂.
- 基于热力学建模,从DNA序列预测增强剂活性.
- 在干扰中,以确定TF增强剂相互作用.
- 与实验增强剂-促进剂相互作用数据的整合.
- 确定乳腺癌相关序列变异的优先级和机制验证.
主要成果:
- 开发了能够根据序列特征区分转录增强剂的模型.
- 确定了特定的TF及其在ERα转录程序中的作用,并得到了现有文献的支持.
- 通过预测TF增强剂关系和整合实验数据,构建了一个基因调控网络.
- 成功地确定了乳腺癌相关序列变异的优先级并提供了机制解释.
- 实验验证了三种序列变体的预测机制.
结论:
- 基于序列的建模是一种强大的方法,可以理解ERα的增强器功能和调节.
- 开发的模型提供了对乳腺癌发育和进展的机制性见解.
- 这项工作为识别和功能性注释癌症相关监管元素中的遗传变异提供了一个框架.
相关概念视频
RNA Polymerase II Accessory Proteins
9.2K
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...
9.2K
The Eukaryotic Promoter Region
3.0K
3.0K
Co-activators and Co-repressors
7.3K
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
7.3K
Master Transcription Regulators
6.9K
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...
6.9K
Cis-regulatory Sequences
9.8K
Cis-regulatory sequences are short fragments of non-coding DNA that are present on the same chromosomes as the genes that they regulate. These fragments serve as binding sites for transcriptional regulators, proteins that are responsible for controlling gene transcription and differential gene expression across cell types in eukaryotes. Cis-regulatory sequences can be close to the gene of interest or thousands of bases away in the DNA sequence; however, those sequences that are further away are...
9.8K
Cell Specific Gene Expression
13.6K
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
13.6K


