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The HIRA gene is highly conserved in many species and controls cell division predominantly by regulating the packaging of DNA and associated proteins (chromatin remodeling). Regulation of cellular division is an important aspect of proper development. In humans, the developmental abnormality known as DiGeorge syndrome is characterized by several facial and cardiac malformations. These developmental abnormalities are caused by improper regulation of the human HIRA gene located on chromosome 22.
Regulation of cell division also has important implications for the treatment of cancer. When cells lose regulation and continuously proliferate, a tumor forms. Understanding how cell proliferation can be suppressed is crucial to the discovery of new cancer treatment options. A key event that leads to the suppression of cell division is a mechanism known as cellular senescence. When a cell enters senescence, the DNA is packaged tightly and is turned “off”. In the senescent state, cells remain alive but do not divide. HIRA is a major contributor to cellular senescence since DNA packaging is required to keep genes turned “off”. In addition to HIRA, another gene known as ASFI, is also required to suppress cell division. The protein products encoded by HIRA and ASFI have been shown to physically interact in animal systems and are required for proper DNA packaging and cellular senescence.
Using the mustard plant Arabidopsis thaliana as a model system, the focus of my work is to understand how hira functions in the regulation of gene expression and chromatin formation. As observed in mammal systems, mutations in the hira gene of Arabidopsis results in improper development. These plants have leaf and floral phenotypes that suggest cell division is not properly regulated. Arabidopsis also has two copies of the ASFI gene. It is not yet clear what role these genes have in plants or if plant cells undergo cellular senescence as observed in mammalian cells.
Using Arabidopsis thaliana as a model system to address the role of HIRA has several advantages. From an experimental standpoint Arabidopsis requires little space and has a life cycle of 12 weeks. In addition, the genome has been fully sequenced and transgenic plants can easily be made. These features make Arabidopsis an attractive model system for molecular and genetic analysis. From a developmental standpoint Arabidopsis is a good system because there is no cell migration during plant development. Thus in plants, the developmental defects observed in HIRA mutants are truly due to improper gene regulation and cell division, not cell migration. Plants also differ from animals because differentiation occurs throughout the entire life cycle. Lateral organs, such as leaves and flowers, are constantly produced. This is in contrast to mammals, where all lateral organs (arms and legs) emerge prior to birth. Emergence of lateral organs, in plants and animals, is dependent on complex gene regulation that promotes differentiation of stem cells. Finally, hira is highly conserved among species suggesting that gene regulation via chromatin remodeling is evolutionarily significant. While there are differences between plant and animal development it is highly likely that the mechanism of regulating gene expression via chromatin remodeling will be the same in both plants and animals. Therefore, the knowledge gained from analyzing HIRA gene function in plants can be applied to animal systems.
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