? Hematopoiesis involves an intricate pattern of gene expression that is programmed in early precursor cells to fully differentiated cell types, and the whole pathway represents an intricate example of tissue specific gene expression. The tissue specificity of mammalian gene expression is determined by the levels of trans-acting factors, as well as by epigenetic events that allow both the long-term control and the flexibility required by development. The complexity of mammalian gene expression is realized from the limited number (ca 28,000) of genes in human and mouse genomes by a series of mechanisms that often results in the production of several transcripts from a single gene under tight control in different stages of differentiation. We have been studying the mouse folylpolyglutamate synthetase (fpgs) gene as an example of a genetic locus in which two distinct gene products are produced from two distantly placed promoters in a tissue-specific pattern. This gene is particularly interesting because any given tissue produces transcript from only one promoter, although tissues that express from the one or the other or neither are known. Our studies on the mouse fpgs gene have indicated that there are layers of coordinated control of the two promoters, but that events at the two promoters follow very different patterns. My initial studies have recently shown that this gene constitutes one of the very few known examples of transcriptional interference in an endogenous gene, and also one of the few promoters for which tissue-specific silencing correlates with DNA methylation at a CpG-sparse promoter in normal tissues. These studies have also raised the fundamentally important point that transcriptional initiation complexes are poised over at least some promoters both in tissues that produce a mature transcript and in those which do not produce detectable transcript. The focus of this proposal is to explore how DNA methylation and transcriptional interference contribute to promoter choice at the mouse fpgs gene in a tissue-specific fashion, and to determine whether and the extent to which the phenomena we see integrating control at this single two promoter gene capture general trends in control of gene expression across the mouse genome. A central aspect of human biology is the programming of information present in a single fertilized cell that encodes what proteins are expressed in every cell in the adult human being. Such a tissue-specific expression pattern is seen nowhere as clearly as in the development of the blood cells. In this application, I propose to study how modification of DNA and of a class of DMA-bound proteins (histones) directs this tissue specific information flow and memory. ? ? ? ? ?
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| Rothbart, Scott B; Racanelli, Alexandra C; Moran, Richard G (2010) Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas. Cancer Res 70:10299-309 |
| Racanelli, Alexandra C; Rothbart, Scott B; Heyer, Cortney L et al. (2009) Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res 69:5467-74 |
