The overall goal of this program is to understand the domain structure of heterochromatin and the mechanism underlying the function of heterochromatin boundary elements in the model organism Saccharomyces cerevisiae. In S. cerevisiae, transcriptionally silent chromatin at the HML and HMR loci is the yeast equivalent of metazoan heterochromatin, and is established by cis-acting silencers. To address how heterochromatin is restricted to limited regions, the domain structure of the silent HML locus will be defined by examining the profile of repression of a reporter gene inserted in positions within and around HML. Moreover, the mechanism underlying why certain silencers establish silent chromatin only in one direction but others function in both directions will be examined by testing if this is determined by the sequence features of the silencer or its genomic context. To understand the molecular mechanism of chromatin boundary elements that delimit chromosome domains, the function of yeast heterochromatin boundary elements that can block the spread of silent chromatin will be extensively studied. This will be achieved by examining the functions of factors involved in the boundary activity and testing models for boundary activity. The possible functional conservation of boundary elements between yeast and higher eukaryotes will also be investigated by examining if yeast boundary elements function in higher cells and vice versa. These studies should shed light on the mechanism of heterochromatin related gene regulation in higher eukaryotes. One such regulation is chromosomal imprinting in mammals that plays an important role in embryonic development and underlies the variable expression of a variety of human disorders and sporadic cancers. Chromatin boundary elements can be very useful in a variety of practical applications including shielding reporter genes against the repressive effect of heterochromatin in cells and transgenic animals, as well as the construction of viral vectors for gene therapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Carter, Anthony D
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University of Nebraska Lincoln
Schools of Earth Sciences/Natur
United States
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Zhang, Ling; Chen, Hua; Bi, Xin et al. (2013) Detection of an altered heterochromatin structure in the absence of the nucleotide excision repair protein Rad4 in Saccharomyces cerevisiae. Cell Cycle 12:2435-42
Zhang, Xinmin; Yu, Qun; Olsen, Lars et al. (2012) Functions of protosilencers in the formation and maintenance of heterochromatin in Saccharomyces cerevisiae. PLoS One 7:e37092
Bi, Xin (2012) Functions of chromatin remodeling factors in heterochromatin formation and maintenance. Sci China Life Sci 55:89-96
Yu, Qun; Olsen, Lars; Zhang, Xinmin et al. (2011) Differential contributions of histone H3 and H4 residues to heterochromatin structure. Genetics 188:291-308
Yu, Qun; Zhang, Xinmin; Bi, Xin (2011) Roles of chromatin remodeling factors in the formation and maintenance of heterochromatin structure. J Biol Chem 286:14659-69
Yu, Qun; Kuzmiak, Holly; Olsen, Lars et al. (2010) Saccharomyces cerevisiae Esc2p interacts with Sir2p through a small ubiquitin-like modifier (SUMO)-binding motif and regulates transcriptionally silent chromatin in a locus-dependent manner. J Biol Chem 285:7525-36
Hassan, Yousef I; Moriyama, Hideaki; Olsen, Lars J et al. (2009) N- and C-terminal domains in human holocarboxylase synthetase participate in substrate recognition. Mol Genet Metab 96:183-8
Yu, Qun; Kuzmiak, Holly; Zou, Yanfei et al. (2009) Saccharomyces cerevisiae linker histone Hho1p functionally interacts with core histone H4 and negatively regulates the establishment of transcriptionally silent chromatin. J Biol Chem 284:740-50
Yu, Qun; Elizondo, Susan; Bi, Xin (2006) Structural analyses of Sum1-1p-dependent transcriptionally silent chromatin in Saccharomyces cerevisiae. J Mol Biol 356:1082-92
Yu, Qun; Sandmeier, Joseph; Xu, Hengping et al. (2006) Mechanism of the long range anti-silencing function of targeted histone acetyltransferases in yeast. J Biol Chem 281:3980-8

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