MECHANISMS OF EPIGENETIC REGULATION IN EARLY CELL FATE DETERMINATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人体由数百种特殊的细胞形式组成，从皮肤、肌肉到血液。所有这些细胞都来自同一个祖先(即受精卵)，并共享相同的遗传信息。在发育过程中，如何在不涉及DNA序列变化的情况下对特定类型的细胞进行编程和维持，这是一个深刻的生物学问题。 混合系白血病(MLL)蛋白是组蛋白甲基转移酶，在决定细胞命运和耐药的儿童白血病(MLL)的发病机制中起着关键作用。MLL蛋白通过在组蛋白上“写”甲基标记来启动特定的基因集，将干细胞或祖细胞转化为特定的细胞。在混合血型白血病的儿童中，MLL蛋白表达失调，导致对血细胞早期发育至关重要的基因表达不足，以及将造血祖细胞转化为白血病癌细胞的基因过度表达。细胞间或细胞内的电路或环境信号如何与MLL蛋白相互作用，在空间和时间上精确地将MLL靶向正确的基因，这方面的研究还很少。为了了解这一点，我们计划用串联质谱仪来确定胚胎干细胞分化过程中MLL的动态结合伙伴。如果成功，这项研究将建立一个在ES细胞和分化过程中MLL蛋白的动态相互作用组图，这不仅将促进我们对细胞命运决定的理解，而且还将提供可能的药物靶点，以改善MLL的治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The human body is made of hundreds of specialized cell forms ranging from skin, muscle to blood. All of these cells arise from a single ancestor (i.e. the zygote) and share the same genetic information. How specialized cell types are programmed and maintained during development, in a way that does not involve changes in DNA sequence, is a profound biological question. The mixed-lineage leukemia (MLL) proteins, which are histone methyltransferase enzymes, play a critical role in cell fate determination and pathogenesis of a drug-resistant form of childhood leukemia (mixed-lineage leukemia, MLL). MLL proteins turn on specific sets of genes by "writing" methyl marks at histones, transforming stem or progenitor cells to lineage specific cells. In children with mixed-lineage leukemia, MLL proteins are misregulated, which causes under expression of genes important for early development of blood cells and over expression of genes that transform blood progenitor cells to leukemia cancer cells. How inter- or intracellular circuitry or environmental cues interact with MLL proteins to precisely target MLL to the right genes in space and time is poorly studied. To gain understanding, we plan to determine the dynamic binding partners of MLL during the process of ES differentiation using tandem mass spectrometry. If successful, this research will generate a dynamic interactome map of MLL proteins in ES cells and during differentiation, which will not only advance our understanding of cell fate determination, but also provide possible drug targets that will improve treatment of MLL.