GENE REGULATION GOVERNING T LYMPHOCYTE FATE DECISIONS

描述（由申请人提供）：摘要：细胞谱系的发展过程中的决定需要严格的基因调控的复杂网络的多个转录因子和协作因子。在命运决定过程中，关键转录因子（TF）驱动前体进入 一个血统，同时灭活“替代命运基因”。沉默状态的一个子集的“交替命运基因”是遗传保持通过表观遗传沉默。表观遗传沉默对正常细胞发育具有全球重要性，并且通常在许多类型的癌症中发生改变。表观遗传沉默的建立涉及介导抑制性组蛋白甲基化和DNA甲基化的酶活性的募集。这些酶活性被认为是由特定组的TF以基因座特异性方式递送的。然而，这些转基因驱动细胞命运决定，然后建立表观遗传沉默的机制还没有完全理解。 在这个提议中，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身份的表观遗传修饰剂之间的串扰。T淋巴细胞发育是一个很好的系统来解决这些问题，因为我们强大的背景知识的发展过程和要求的TF。具体来说，我们将研究Runx转录因子在基因阻遏的命运决定和表观遗传沉默的“替代命运基因”的背景下的功能。我们的努力将集中在Runx蛋白及其相互作用因子之间的功能合作的研究，驱动和稳定的命运选择过程。由于Runx蛋白参与许多细胞类型的正常发育，并且它们的功能在白血病中经常改变，因此通过我们对T细胞发育期间Runx介导的遗传和表观遗传调控的研究获得的知识将为广泛用于许多细胞类型的稳定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见解。

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.