The switch between differentiation and growth is precisely regulated in all organisms. Loss of this control in humans can lead to cancer. Differentiation/growth switches are generally controlled by multiple extracellular signals, but analyzing the relationship between different controls is difficult in most systems. A simple prototype exists in diploid yeast, where three different types of control (cell cycle, glucose and acetate interact to regulate the switch between growth and meiosis. Yeast genetics provides a powerful tool for analyzing these different layers of control both separately and in combination. A central feature of growth/differentiation switches is that the two programs are mutually exclusive: cells must shut down one program to undergo the other. A recent finding the lab sheds light on this mechanism: the same proteins that trigger growth (cyclins) also repress initiation of meiosis. By measuring expression of specific meiotic regulators under conditions where cyclins are either absent or overexpressed, the mechanisms underlying repression of meiosis by cyclins will be defined (Specific Aim 1). The investigator has discovered the IME1 transcription is regulated like a 3-position switch; it is completely repressed under growth conditions, expressed to high levels under sporulation conditions, and expressed to moderate levels under conditions of carbon deprivation. The moderate level IME1 expression causes some cells to undergo recombination without chromosome segregation. This novel mechanism for transcriptional regulation, which involves interactions between several levels of control, will be dissected using a combination of yeast genetics and molecular biology (Specific Aim 2). Extracellular signals are generally considered to act at the beginning of a differentiation program, triggering a continuous progression of cellular changes. The investigator made the intriguing discovery that meiosis in yeast responds to extracellular signals at two distinct stages: prior to premeiotic DNA synthesis (early) and prior to chromosome segregation (late), and that the regulation at the two stages is different. To further examine this two-step control of differentiation, genes involved in nutritional control of late meiotic events are being identified, and their interactions with known meiotic regulators characterized (Specific Aim 3).
| Gray, Misa; Kupiec, Martin; Honigberg, Saul M (2004) Site-specific genomic (SSG) and random domain-localized (RDL) mutagenesis in yeast. BMC Biotechnol 4:7 |
| Honigberg, Saul M; Purnapatre, Kedar (2003) Signal pathway integration in the switch from the mitotic cell cycle to meiosis in yeast. J Cell Sci 116:2137-47 |
| Purnapatre, Kedar; Honigberg, Saul M (2002) Meiotic differentiation during colony maturation in Saccharomyces cerevisiae. Curr Genet 42:1-8 |
| Gray, M; Honigberg, S M (2001) Effect of chromosomal locus, GC content and length of homology on PCR-mediated targeted gene replacement in Saccharomyces. Nucleic Acids Res 29:5156-62 |
