GENE REGULATION GOVERNING T LYMPHOCYTE FATE DECISIONS

描述(由申请人提供)：摘要：发育过程中的细胞谱系决定需要由多个转录因子和协作因子组成的复杂网络进行严格的基因调控。在命运决定过程中，关键转录因子(TF)驱动前体进入 一种血统，同时灭活“另类命运基因”。“另类命运基因”子集的沉默状态是通过表观遗传沉默遗传地维持的。表观遗传沉默对正常细胞发育具有全球重要性，在许多类型的癌症中普遍改变。表观遗传沉默的建立涉及调节抑制性组蛋白甲基化和DNA甲基化的酶活性的重新招募。这些酶的活性被认为是由特定的转铁蛋白以特定的位点方式传递的。然而，这些转录因子驱动细胞命运决定，然后建立表观遗传沉默的机制还不完全清楚。在这项提案中，我们将研究驱动T细胞谱系选择的关键TF和最终建立细胞谱系特性的表观遗传修饰物之间的串扰。T淋巴细胞发育是解决这些问题的一个很好的系统，因为我们对发育过程和对转录因子的要求有很强的背景知识。具体地说，我们将在命运决定和表观遗传沉默的背景下研究RUNX转录因子在基因抑制中的功能。我们的努力将集中在研究RUNX蛋白和它们相互作用的因素之间的功能协作，这些因素驱动和稳定命运选择过程。由于RUNX蛋白参与多种细胞类型的正常发育，其功能在白血病中经常改变，通过我们对RUNX介导的T细胞发育过程中的遗传和表观遗传调控的研究获得的知识将为深入了解广泛应用于许多细胞类型的稳定的基因调控机制以及导致癌症的改变的遗传程序提供实质性的见解。 与公共卫生相关：干细胞/祖细胞不断产生不同类型的细胞，以维持正常的细胞室。在细胞分化过程中，一组特定的基因被转录因子激活或关闭，这些不同的基因表达状态被稳定地保持。在这项研究中，我建议研究对维持动物和人类细胞类型多样性至关重要的基因调控机制。

DESCRIPTION (provided by applicant): Abstract: Cell lineage decisions during development require strict gene regulation by complex networks of multiple transcription factors and collaborating factors. During fate decisions, key transcription factors (TFs) drive precursors into one lineage while inactivating "alternative fate genes". Silenced states of a subset of "alternativ fate genes" are heritably maintained through epigenetic silencing. Epigenetic silencing is globally important for normal cell development and commonly altered in many types of cancers. Establishment of epigenetic silencing involves recruitment of enzyme activities mediating repressive histone methylation and DNA methylation. These enzyme activities are thought to be delivered by specific sets of TFs in a locus- specific manner. However, the mechanisms by which these TFs drive cel fate decisions and then establish epigenetic silencing are not completely understood. In this proposal, we will study crosstalk between key TFs driving T cell lineage choices and epigenetic modifiers that ultimately establish cell lineage identities. T lymphocyte development is an excellent system to tackle these questions because of our strong background knowledge on developmental processes and requirements for TFs. Specifically, we will study functions of Runx transcription factors in gene repression in the context of fate decisions and epigenetic silencing of "alternative fate genes". Our efforts will be focused on study of functional collaborations between Runx proteins and their interacting factors that drive and stabilize the fate choice processes. Because Runx proteins are involved in normal development of many cell types, and their functions are frequently altered in leukemia, knowledge obtained through our study of Runx-mediated genetic and epigenetic regulation during T cell development would provide substantial insights into stable gene regulation mechanisms widely used in many cell types as well as altered genetic programs causing cancers. PUBLIC HEALTH RELEVANCE: Diverse cell types are continuously generated from stem/progenitor cells to maintain functional cell compartments. During cell differentiation, a specific set of genes is turned-on or -off by transcription factors, and these distinct states of gene expression are stably maintained. In this study, I propose to investigate the gene regulatory mechanisms that are critical for maintaining cell type diversity in animals and humans.