在转录因子RUNX1中的编码变体的接口引导的表型化
Kivilcim Ozturk1, Rebecca Panwala2, Jeanna Sheen3
1Division of Medical Genetics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.
Cell reports
|July 5, 2024
概括
解释RUNX1突变是很困难的. 功能查确定了野生类型,功能丧失和低形态变体,改善了变体分类和理解突变影响.
科学领域:
- 基因组学就是基因组学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 解释单基因误解突变,特别是像RUNX1这样的癌症相关基因,是一个重大挑战.
- RUNX1突变与各种血液性恶性瘤有关,但它们的确切功能后果往往不清楚.
研究的目的:
- 使用可扩展的选方法,以功能性地表征RUNX1误解突变.
- 根据它们对细胞程序和下游基因表达的影响对突变进行分类.
- 在RUNX1.1.中改进不确定的意义变体 (VUS) 的分类.
主要方法:
- 通过测序 (SEUSS) 部署可扩展的功能选,一种Perturb-seq方法,以引入和评估115个RUNX1突变.
- 对单细胞RNA测序资料的分析,将突变分类为野生类型 (WT) 类型,功能丧失 (LoF) 类型和低形态组.
- 函数类别的验证和VUS预测的计算分类器培训的直角测试.
主要成果:
- 确定RUNX1突变的三个不同的功能类别:类似WT的,类似LoF的和低形态的.
- 类似LoF的变体在DNA结合部位被丰富,在癌症中经常复发,尽管复发不仅仅预测功能.
- 低形变体影响了蛋白质相互作用,影响了与神经生长因子 (NGF) 反应和中性粒细胞因子招募相关的基因表达.
- 在接近差异表达基因的可访问DNA中发现了RUNX1结合基因.
- 16个VUS的重新分类和开发一个分类器来预测103个额外的变体的功能.
结论:
- 可扩展的功能查对于解释像RUNX1.1.这样的基因中的误解突变是有效的.
- 仅仅突变的复发不足以预测功能影响;功能分类至关重要.
- 了解LoF类和低形态变体的独特功能影响,可以了解RUNX1驱动的表型.
- 准蛋白相互作用为定义误解突变的表型景观提供了一个有希望的途径.
相关概念视频
General Transcription Factors
5.2K
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...
5.2K
Inheritance of Chromatin Structures
6.2K
Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying...
6.2K
Combinatorial Gene Control
8.3K
Combinatorial gene control is the synergistic action of several transcriptional factors to regulate the expression of a single gene. The absence of one or more of these factors may lead to a significant difference in the level of gene expression or repression.
The expression of more than 30,000 genes is controlled by approximately 2000-3000 transcription factors. This is possible because a single transcription factor can recognize more than one regulatory sequence. The specificity in gene...
The expression of more than 30,000 genes is controlled by approximately 2000-3000 transcription factors. This is possible because a single transcription factor can recognize more than one regulatory sequence. The specificity in gene...
8.3K
Transcription Factors
75.8K
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...
75.8K
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
Pleiotropy
40.4K
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
40.4K


