One interest of the Fire lab is studying the mechanisms of cell fate choice during development, in particular the asymmetric generation of cell fates. The researchers use C. elegans as an experimental organism because of its genetics and relative simplicity of development.

The scientists’ studies of germ line/soma decisions have focused on questions about how these two cell populations differ in their capacities for gene expression. It appears that germ cells have a number of highly active mechanisms to limit the expression of somatically expressed genes. Some of these mechanisms may act at the level of gene context or chromatin structure. Researchers in the lab are interested in understanding how this regulation is mediated and what features of gene expression allow specific cells to maintain “germ line” capacity to produce subsequent generations of the organism.

Much of the analysis of somatic fates has focused on the formation of different muscle types during embryonic and post-embryonic development. Studies of muscle development have been facilitated by the wealth of available probes and assays for morphology, function, and terminal differentiation. Myogenic decisions during embryogenesis and larval development result in a variety of different muscle types in C. elegans. The lab’s analysis is directed toward understanding the general processes responsible for the choice of cell type and subsequent tissue patterning, and addresses the following questions: What types of factors control and carry out decisions to undergo myogenesis? What is the molecular nature of the blastomere identities set up in the early embryo and “remembered” during cell proliferation? How is lineage information interpreted to determine cell fate, and are there similar activities regulating myogenesis for nematode and analogous vertebrate muscles?

The researchers are also involved in studies of stable gene activation and gene silencing. Cellular processes that allow stable maintenance of gene expression patterns are tightly linked to the determination and maintenance of cell fates. The numerous biochemical mechanisms by which genes are stably maintained in "on" or "off" states thus form a basis for much of developmental biology. Some mechanisms for stable modulation of gene expression are at least partly understood. They involve transcriptional or post-transcriptional feedback loops with autoregulation by small groups transacting regulatory factors. In early attempts to stably manipulate the C. elegans genome by using DNA-mediated transformation, the investigators encountered a number of difficulties that were not readily explained by such gene-specific regulatory mechanisms. Subsequent analysis of these processes has revealed a variety of unexpected control mechanisms that can be triggered by aberrant aspects of RNA structure (extended regions of duplex), or by aberrant aspects of DNA organization (extensively repeated DNA sequences). These mechanisms appear to benefit the genome in at least two distinct ways: by expanding the available repertoire of developmental control mechanisms and by providing a general defense against foreign or unwanted gene expression (such as transposons and viruses). Our studies of long-term and epigenetic silencing are aimed at understanding the underlying molecular mechanisms and the contributions of these mechanisms to developmental control and the maintenance of a functional genome.

"Photo shows the use of transgenic technology to track a single cell lineage during development. In these animals, production of a reporter protein (which makes a blue color) is driven by control signals from the C. elegans hlh-8 gene (normally expressed in a specific mesodermal cell lineage, the M lineage). Members of the Fire lab use animals from this transgenic line to accurately assess the fate of cells derived from the M lineage".