MECHANISMS OF EPIGENETIC REGULATION IN EARLY CELL FATE DETERMINATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人体由数百种特殊的细胞组成，从皮肤，肌肉到血液。 所有这些细胞都来自一个祖先（即受精卵），并共享相同的遗传信息。 在发育过程中，如何以不涉及DNA序列变化的方式编程和维持专门的细胞类型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，在儿童白血病（MLL）耐药形式的细胞命运决定和发病机制中起着关键作用。 MLL蛋白通过在组蛋白上“写”甲基标记来开启特定的基因组，将干细胞或祖细胞转化为谱系特异性细胞。 在患有混合谱系白血病的儿童中，MLL蛋白质被错误调节，这导致对血细胞早期发育重要的基因的表达不足和将血液祖细胞转化为白血病癌细胞的基因的过度表达。 间或细胞内回路或环境线索如何与MLL蛋白相互作用，以在空间和时间上将MLL精确地靶向正确的基因，研究得很少。 为了获得理解，我们计划使用串联质谱法确定ES分化过程中MLL的动态结合伴侣。 如果成功，这项研究将产生一个动态的相互作用图谱的MLL蛋白在ES细胞和分化过程中，这不仅将促进我们的理解细胞命运的决定，而且还提供可能的药物靶点，将改善治疗MLL。

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.