叉头盒蛋白O1的基因组结合模式揭示了它在心脏缩中的独特作用
Jessica Pfleger1, Ryan C Coleman1, Jessica Ibetti1
1Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
Circulation
|July 10, 2020
概括
叉头盒蛋白O1 (FoxO1) 通过调节基因表达和RNA聚合酶II动态驱动心脏缩. 针对FoxO1可能为心脏缩提供治疗策略.
科学领域:
- 心血管生物学
- 分子生物学
- 基因调控
背景情况:
- 心脏缩包括显著的基因表达变化和心肌细胞大小增加.
- 这些变化的基础是RNA聚合酶II (pol II) 的活性,包括de novo招募和转录延长.
- 转录因子,如叉头盒蛋白O1 (FoxO1) 在心脏缩过程中对这些pol II过程的差异调节的作用在很大程度上是未知的.
研究的目的:
- 研究FoxO1在心脏缩生长过程中的基因表达和pol II动态调节中的作用.
- 在高刺激下探索FoxO1在心脏中的基因调节范围.
主要方法:
- 在小鼠心脏上进行了FoxO1染色体免疫沉深度测序 (ChIP-seq),小鼠心脏接受了异质醇注射或横向主动脉收缩.
- 将FoxO1 ChIP-seq数据与pol II ChIP-seq数据集成,以分析与pol II招募和延长有关的FoxO1结合.
- 在心肌细胞缩的背景下,FoxO1功能在体外和体内被评估,使用敲除或删除策略.
主要成果:
- 在心脏缩期间FoxO1染色体结合增加,与其程度呈正相关性.
- 在横向大动脉收缩后,FoxO1与高百分比的心脏表达基因的促进体结合.
- 在由pol II de novo招募,损失和暂停释放调节的基因中,FoxO1结合升高,在后者中起重要作用.
- 预防心肌细胞过敏生长和减少关键诱导基因的表达.
结论:
- FoxO1通过调节pol II de novo招募和暂停释放来调节心脏缩的增长.
- 在压力过载后,大多数FoxO1结合,pol II调节的基因都涉及到pol II暂停释放.
- 这些发现突显了FoxO1在心脏缩中的广泛转录调节作用,表明其作为治疗点的潜力.
相关概念视频
01:30General Transcription Factors
6.5K
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...
6.5K
01:27Specialized Characteristics of Cardiac Muscles
3.8K
The primary role of cardiac muscles is to propel blood throughout the cardiovascular system. The cardiac muscle cells, or cardiomyocytes, exhibit specialized characteristics that allow them to perform this function.
Cardiac muscle cells are smaller than skeletal muscles, averaging 10–20 mm in diameter and 50–100 mm in length. However, they have large energy demands for continuous contraction and relaxation. This energy is almost exclusively derived from aerobic metabolism of energy...
Cardiac muscle cells are smaller than skeletal muscles, averaging 10–20 mm in diameter and 50–100 mm in length. However, they have large energy demands for continuous contraction and relaxation. This energy is almost exclusively derived from aerobic metabolism of energy...
3.8K
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
249
Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
249
02:23Master Transcription Regulators
7.6K
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...
7.6K
01:29Pathophysiology of Cardiac Performance
1.2K
Typical heart performance is influenced by heart rate, rhythm, myocardial contraction, and metabolism or blood flow. The cardiac muscle exhibits distinct electrophysiological features, including pacemaker activity and calcium channel control, which play a vital role in the heart's response to various drugs. The autonomic nervous system, comprising the sympathetic and parasympathetic branches, regulates heart rate. Sympathetic activation increases heart rate, while parasympathetic activation...
1.2K
01:58Cell Specific Gene Expression
16.1K
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...
16.1K