MAPK regulation of the epigenome during mast cell differentiation

人类和其他动物的骨髓含有干细胞，可以成为免疫系统的各种细胞类型。这个过程称为分化，产生特定类型的免疫细胞，并需要由细胞信号传导事件引发的基因表达变化。对干细胞的灵活性很重要的基因被关闭，而对成熟免疫细胞很重要的基因被激活。基因表达的这些变化涉及染色质或DNA的稳定结构变化，这一过程称为表观遗传基因调节。特定的基因通过非常紧密地包装它们而被关闭，这样它们在染色质中就无法接近，而其他基因则通过更松散地包装以便于接近而被打开。组蛋白乙酰化和DNA甲基化过程是主要贡献者。 肥大细胞是一种在防御中起重要作用的免疫细胞类型，但我们还不完全了解它们如何与干细胞分化。我们知道，有丝分裂原活化蛋白激酶（MAPK）通路是肥大细胞分化的一种重要信号传导途径。MAPK信号传导与其他细胞类型分化过程中的表观遗传变化有关，我们知道它被激活并且对肥大细胞分化很重要。虽然在肥大细胞分化中发现了一些表观遗传变化，但控制它的信号转导尚不清楚。这些事件之间的联系代表了我们理解上的一个重大差距，并突出了我提出的研究的新奇。我的研究小组已经确定了几种表观遗传酶在分化肥大细胞中的激活。我们假设MAPK信号有助于表观遗传酶的激活，表观遗传酶导致肥大细胞基因在分化过程中被打开，干细胞基因在分化过程中被关闭。 为了确定MAPK信号传导在肥大细胞分化表观遗传学中的作用，我们将进行实验以满足以下3个目标： 1)确定肥大细胞分化过程中MAPK信号在组蛋白乙酰化中的重要性。 2)评估肥大细胞分化过程中MAPK信号在DNA甲基化中的作用。 3)研究MAPK蛋白在肥大细胞分化和活化过程中进入细胞核的意义。 预期意义：这项研究的总体目标是提高我们对MAPK蛋白在肥大细胞分化过程中如何调节核内基因表达的理解。MAPK信号在多种细胞功能中是高度保守和重要的，包括生长、分化、发育、应激反应和细胞死亡。鉴于这种功能作用的广度，所获得的结果可能具有广泛的生物学应用。这项工作将增强我们对细胞信号传导机制和表观遗传基因调控之间联系的看法，这是自然科学研究的一个新兴领域。

Bone marrow of humans and other animals contains stem cells that can become each of the various cell types of the immune system. This process, called differentiation, creates specific types of immune cells and requires changes in gene expression that are initiated by cell signaling events. Genes important for the flexible nature of the stem cell are turned off, while genes important to the mature immune cell are activated. These changes in gene expression involve stable structural changes to chromatin or DNA in a process called epigenetic gene regulation. Specific genes are turned off by packaging them very tightly so that they are inaccessible within the chromatin, while others are turned on by packaging more loosely to ease access. The processes of histone acetylation and DNA methylation are major contributors. Mast cells are an immune cell type that plays important roles in defense, but we do not fully understand how they differentiate from stem cells. One type of signaling that we know is important for the differentiation of mast cells is the mitogen-activated protein kinase (MAPK) pathway. MAPK signaling is connected to epigenetic changes during the differentiation of other cell types and we know that it is activated and important for mast cell differentiation. While some epigenetic changes have been found in mast cell differentiation, the signaling that controls it is unknown. The link between these events represents a major gap in our understanding, and highlights the novelty of my proposed research. My research team has identified the activation of several epigenetic enzymes in differentiating mast cells. We hypothesize that MAPK signals contribute to activation of epigenetic enzymes which cause mast cell genes to be turned on and stem cell genes to be turned off during differentiation. To determine the role of the MAPK signaling in mast cell differentiation epigenetics, we will conduct experiments to meet the following 3 objectives: 1) Determine the importance of MAPK signaling in histone acetylation during mast cell differentiation. 2) Assess the role of MAPK signaling in DNA methylation during mast cell differentiation. 3) Examine the significance of MAPK proteins entering the nucleus during mast cell differentiation and activation. Expected significance: The overall objective of the proposed research is to improve our understanding of how MAPK proteins regulate gene expression within the nucleus during mast cell differentiation. MAPK signaling is highly conserved and important in a wide variety cell functions, including growth, differentiation, development, response to stress, and cell death. Given this breadth of functional roles, the results obtained could have broad biological applications. This work will enhance our perspective on the connections between cell signaling mechanisms and epigenetic gene regulation, an emerging area of research in the natural sciences.