Regulation of gene expression is crucial for every function carried out by the cell, from cell growth and proliferation to the ability of the cell to respond to its ever-changing environment. Hence, understanding cellular function and dysfunction is dependent upon deciphering these gene regulatory mechanisms. This is particularly challenging in the case of eukaryotic genes, which are often interrupted by long stretches of noncoding sequences (introns). These are removed from the newly synthesized RNA, and the remaining sequences (exons) are ligated together to form a mature messenger RNA. This process, pre-messenger RNA splicing, is carried out by the spliceosome made up of 5 small nuclear RNAs and over 100 proteins. The spliceosome undergoes dynamic and coordinated rearrangements in order to recognize splicing signals in the RNA and catalyze the splicing reaction. Remarkably, the spliceosome assembles onto the pre-mRNA co-transcriptionally, while the RNA polymerase is actively engaged with the chromatin template. This close spatial and temporal proximity of splicing and transcription raise the intriguing possibility that assembly of the spliceosome onto pre-mRNA may be influenced by transcription, and/or the state of the chromatin and vice versa; splicing may influence transcription and chromatin modification. The goal of our research is to decipher the workings of this elegant ribonucleoprotein machine. Moreover, we seek to understand how regulation of RNA splicing and other RNA processing reactions allows the cell to respond to its environment.
The Erika Matunis Laboratory studies the stem cells that sustain spermatogenesis in the fruit fly Drosophila melanogaster to understand how signals from neighboring cells control stem cell renewal or differentiation. In the fruit fly testes, germ line stem cells attach to a cluster of non-dividing somatic cells called the hub. When a germ line stem cell divides, its daughter is pushed away from the hub and differentiates into a gonialblast. The germ line stem cells receive a signal from the hub that allows it to remain a stem cell, while the daughter displaced away from the hub loses the signal and differentiates. We have found key regulatory signals involved in this process. We use genetic and genomic approaches to identify more genes that define the germ line stem cells’ fate. We are also investigating how spermatogonia reverse differentiation to become germ line stem cells again.
The Johnston Lab’s research explores the development of the cells responsible for color vision. Many aspects of development are precisely regimented, with specific sets of genes activated like clockwork to dictate the fate of a cell, including which proteins it will make. But some systems are less meticulous. We found that, in the fly retina, the scattershot distribution of cells that produce different visual pigments is governed by the random activation of a single gene: when the gene is on, one pigment is produced; when it is off, the other is made. My laboratory will determine how each of the two copies of this gene in a retinal cell “decides” whether to switch on or off, and how it communicates this decision to its partner so that both can “agree”—work we plan to extend to the selection of visual pigments in human retinal cells. These findings will deepen our understanding of how random processes contribute to complex networks of gene regulation and how this type of regulation may go awry during ocular disease.