MLL in maintenance and regulation of HOX gene expression

描述（由申请人提供）：MLL首次被发现是因为它涉及导致白血病的染色体易位。MLL是维持靶基因（包括一些成簇的HOX基因）的正确表达所必需的。越来越多的证据表明，MLL通过调节染色质结构来调节基因表达，染色质结构是通过其一些蛋白质结构域的活性以及通过其招募的其他蛋白质来实现的。我们的数据表明，MLL保护Hoxa 9靶基因位点中的特定CpG DNA序列免受甲基化，从而允许典型Hoxa 9和微小RNA前体的基因表达。因此，我们提出了一个新的模型MLL功能。我们认为MLL通过阻止发育过程中CpG岛甲基化来保持其靶基因表达的潜力。MLL对CpG甲基化的保护使基因座保持“开放”，并允许基因在随后的细胞分裂中表达。这种标记不容易改变，因此可以起到维持先前基因表达的记忆的作用。我们将确定MLL在保护DNA甲基化中的作用，MLL CpG DNA结合CXXC结构域对MLL融合功能的特定作用，以及特定microRNA对MLL白血病发生的作用。公共卫生相关性：MLL是一种基因，当涉及染色体重排时，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，即它如何调节其他基因的表达。我们希望进一步研究这种新机制的细节，以促进我们对MLL正常功能以及MLL白血病中这种功能如何改变的理解。

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.