MLL in maintenance and regulation of HOX gene expression

描述（由申请人提供）：MLL最初被发现是因为它与导致白血病的染色体易位有关。MLL是维持靶基因的正常表达所必需的，包括一些聚集性HOX基因。越来越多的证据表明，MLL通过其某些蛋白质结构域的活性以及通过其招募的其他蛋白质来调节染色质结构，从而调节基因表达。我们的数据表明，MLL保护Hoxa9靶基因位点上的特定CpG DNA序列免受甲基化，从而允许典型Hoxa9和microRNA前体的基因表达。因此，我们提出了一种新的MLL函数模型。我们认为MLL通过在发育过程中阻止CpG岛甲基化来保持表达其靶基因的潜力。对CpG甲基化的MLL保护使位点保持“开放”，并允许基因在随后的细胞分裂中表达。这个标记不容易改变，因此可以保持对以前基因表达的记忆。我们将确定MLL在防止DNA甲基化中的作用，MLL CpG DNA结合CXXC结构域与MLL融合功能的特定作用，以及特定microRNA在MLL白血病发生中的作用。公共卫生相关性：MLL是一种基因，当参与染色体重排时，会导致预后非常差的白血病。我们已经确定了MLL的一个新功能，关于它如何调节其他基因的表达。我们希望进一步研究这一新机制的细节，以促进我们对MLL正常功能的理解，以及MLL白血病中这种功能是如何改变的。

DESCRIPTION (provided by applicant): MLL was first identified because it is involved in chromosomal translocations that result in leukemia. MLL is required for maintaining the proper expression of target genes, including some of the clustered HOX genes. There is growing evidence that MLL regulates gene expression by modulating chromatin structure via activity of some of its protein domains as well as through additional proteins that it recruits. Our data demonstrate that MLL protects specific CpG DNA sequences in the Hoxa9 target gene locus from methylation, thereby allowing gene expression, both of canonical Hoxa9 and of a microRNA precursor. We therefore propose a novel model of MLL function. We propose that MLL maintains the potential to express its target genes by preventing CpG island methylation during development. MLL protection from CpG methylation keeps the locus "open" and permissive for gene expression through subsequent cell divisions. This mark is not easily changed and, therefore, can function to maintain memory of previous gene expression. We will determine the role of MLL in protection from DNA methylation, the specific role of the MLL CpG DNA binding CXXC domain to MLL fusion function, and of a specific microRNA to MLL leukemogenesis. PUBLIC HEALTH RELEVANCE: MLL is a gene that, when involved in chromosome rearrangements, causes leukemia with a very poor prognosis. We have determined a new function of MLL with regard to how it regulates expression of other genes. We wish to further study the details of this new mechanism to advance our understanding of how MLL normally functions and how this is changed in MLL leukemia.