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(Eukaryotic gene expression) Control of eukaryotic gene expression and replication; DNA structure; virus evolution.


The fundamental building block of the eukaryotic chromosome is the nucleosome core particle, which consists of 147 bp of DNA and two copies each of four histone proteins.  Recent whole genome studies have shown that nucleosomes are well-ordered with respect to DNA sequence, and these results are in agreement with a large body of earlier work which has shown that nucleosomes are distributed in a non-random fashion along the eukaryotic chromosome. The non-random placement of nucleosomes is thought to play an important role in regulating the genome by controlling the access of regulatory proteins. Our work has centered on the DNA sequence determinants for nucleosome positioning and the role of epigenetic factors in the control of nucleosome positioning and stability.

A novel combination of experimental and bioinformatic approaches was used to show that nucleosome positioning is due to 7 tetranucleotide consensus sequences, which are important for preferred formation of nucleosomes at specific sites along DNA.  The results of this study have important implications for models of sequence-dependent positioning since they suggest that a defined subset of tetranucleotides is involved in preferred nucleosome occupancy and that these tetranucleotides are the major source of the dinucleotide periodicities that are characteristic of positioned nucleosomes.

Methylation of DNA at CpG dinucleotides represents one of the most important epigenetic mechanisms involved in the control of gene expression in vertebrate cells. We conducted nucleosome reconstitution experiments in conjunction with high-throughput sequencing on human and mouse DNA that was unmethylated or methylated in order to investigate the effects of this epigenetic modification on the positioning and stability of nucleosomes. The results demonstrated that a subset of nucleosomes positioned by the tetranucleotide consensuses sequences was sensitive to methylation where the modification increased the affinity of these sequences for the histone octamer. The features that distinguished these nucleosomes from the bulk of the methylation insensitive nucleosomes were an increase in the frequency of CpG dinucleotides and a unique rotational orientation of CpGs such that their minor grooves tended to face toward the histones in the nucleosome rather than away. These methylation-sensitive nucleosomes were preferentially associated with exons as compared to introns while unmethylated CpG islands near transcription start sites became enriched in nucleosomes upon methylation. The results of this study suggest that the effects of DNA methylation on nucleosome stability in vitro can recapitulate what has been observed in the cell and provide a direct link between DNA methylation and the structure and function of chromatin


Ph.D., Purdue, 1973

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