在GATA3串联DNA序列中的转录因子合作性决定了瘤原体增强剂介导的激活
Joana R Costa1, Yang Li1, Nurkaiyisah Zaal Anuar2
1Department of Haematology, UCL Cancer Institute, University College London, London, UK.
Cell reports
|May 16, 2025
概括
突变增强剂通过创建MYB结合部位来激活白血病中的TAL1瘤基因. GATA3被确定为一个关键的调节器,与MYB合作,驱动瘤基因过度表达并支持癌症的发展.
科学领域:
- 分子生物学分子生物学
- 癌症基因组学 癌症基因组学
- 基因规则 基因规则
背景情况:
- 在T细胞淋巴细胞白血病中,TAL1基因经常通过cis调节元件的突变被激活.
- 这些突变通常会为转录因子MYB创建结合点,导致瘤基因过度表达.
- 了解非编码突变如何产生致癌增强剂对于癌症生物学和基因调节洞察至关重要.
研究的目的:
- 为了确定参与增强剂介导的TAL1过度表达的关键转录调节者.
- 阐明转录因子在瘤增强剂功能中的合作机制.
- 了解GATA3在TAL1瘤基因激活和白血病发生中的作用.
主要方法:
- 使用CRISPR-Cas9选方法来确定调节因素.
- 使用CRISPR-Cas9设计了突变增强剂,以研究其功能元素.
- 研究了转录因子结合 (GATA3,MYB),染色质可访问性和蛋白质与蛋白质的相互作用.
主要成果:
- 确定了GATA3作为增强剂介导的TAL1过度表达的关键转录调节器.
- 证明突变增强剂含有对GATA3结合,染色质可访问性和MYB招募至关重要的GATA3合位.
- 表明GATA3稳定了TAL1-MYB相互作用,需要GATA3DNA结合以形成复杂物,支持转录因子合作模式.
结论:
- 通过突变增强剂,GATA3与MYB一起作为一个关键的辅助因子,通过突变增强剂驱动TAL1癌基因激活.
- 转录因子对突变增强剂的合作性是T细胞淋巴细胞白血病中癌基因激活的关键机制.
- 这项研究提供了对增强器功能和白血病发生的见解,突出了潜在的治疗点.
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...
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...
02:13Cooperative Binding of Transcription Regulators
Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome. Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form dimers that...
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...
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...
02:13Cooperative Binding of Transcription Regulators
Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome. Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form dimers that...