Eukaryotic chromosomes are organized into transcriptionally active euchromatic domains and transcriptionally inactive heterochromatic domains. Boundary elements assure separation between these domains by blocking silencers or enhancers activity. While gene expression depends on an euchromatic environment, maintaining heterochromatin integrity is essential for several cellular functions, including accurate chromosome segregation in mitosis, genomic stability and gene silencing. Our research focuses on mechanisms that promote heterochromatin assembly and maintenance at specific chromosomal loci and assure separation between euchromatin and heterochromatin. To address these questions, we constructed synthetic heterochromatin domains at an ectopic site by combining cis-acting silencing elements from the mating-type (mat) locus of fission yeast. Using this experimental system, and monitoring reporter gene expression within the mat locus in different genetic backgrounds, we investigated the requirements of heterochromatization. We also characterized new cis-acting protosilencers, and a novel gene, named epe1, that encodes an evolutionary-conserved jmjC domain protein that modulates heterochromatization. Our analysis suggests that Epe1 counteracts transcription silencing by negatively affecting heterochromatin stability, and that the jmjC domain is essential for Epe1 activity. Remarkably, recent experiments indicate that Epe1 controls chromatin-based gene silencing in an euchromatic context and that it may act as developmental regulator in meiosis. Understanding the role of Epe1 in modulating gene silencing is likely to contribute to our understanding of general mechanisms that control the interplay between histone modifications and chromatin remodeling activities that repress or enhance gene expression. This has broad implications, as several lines of evidence indicate a close link between aberrant histone modifications and human disease, most notably cancer.
Isaac, S., Walfridsson, J., Zohar, T., Lazar, D., Kahan, T., Ekwall, K., and Cohen, A. (2007) Interaction of Epe1 with the heterochromatin assembly pathway in Schizosaccharomyces pombe. Genetics 175: 1549-1560.
Ayoub, N., Noma, K., Isaac, S., Kahan, T., Grewal, S.I. and Cohen, A. (2003) A novel jmjC domain protein modulates heterochromatin in fission yeast. Mol Cell Biol. 23: 4356-4370.
Hall, I.M., Shankaranarayana, G.D., Noma, K., Ayoub, N., Cohen, A., and Grewal, S.I. (2002) Establishment and maintenance of a heterochromatin domain. Science. 297:2232-2237.
Ayoub, N., Goldshmidt, I., Lyakhovetsky, R., and Cohen A. (2000). A fission yeast repression element cooperates with centromere-like sequences and defines a mat silent domain boundary Genetics. 156: 983-994.
Friedman-Ohana, R., Karunker I., and Cohen A. (1999) A RecG-independent nonconservative branch migration mechanism in Escherichia coli recombination. J. Bacteriol., 181:7199-7205.
Ayoub A., Goldshmidt I., and Cohen A., (1999) Position effect variegation at the mating-type locus of fission yeast: A cis-acting element inhibits covariegated expression of genes at the silent and expressed domains. Genetics, 152: 495-508.
Friedman-Ohana, R., Karunker I., and Cohen A. (1998) Chi-dependent intramolecular recombination in Escherichia coli. Genetics, 148: 545-557.
Friedman-Ohana, R. and Cohen, A. (1998) Heteroduplex joint formation in Escherichia coli recombination is initiated by pairing of a 3'-ending strand. Proc. Natl. Acad. Sci. USA 95: 6909-6914.
Thon, G., Cohen A., and Klar A.J.S. (1994) Three additional linkage groups that repress transcription and meiotic recombination in the mating-type region of Schizosaccharomyces pombe. Genetics, 138: 29-38.