Post-transcriptional regulation in development and disease
We are interested in understanding the mechanisms that govern post-transcriptional regulation of gene expression during development and complex disease. We employ a combination of biochemical and molecular genetic methods, bioinformatics, chemical biology, biophysics, and structural analyses in our studies, with a focus on quantitative measurements and correlations between biochemical studies and functional studies in cells and animals. Our research is focused primarily in three areas:
Post-transcriptional regulation of maternal mRNAs in development
Maternal transcripts are produced and reversibly silenced in the early stages of oogenesis. In many animals, zygotic transcription does not begin until several cell divisions have occurred, after a number of patterning and cell fate specification events have taken place. Thus, activation of maternal transcripts by maternal regulatory factors provides the starting point for formation of the body plan. We are dissecting the regulatory circuitry that guides establishment and decoding of the maternal load in C. elegans.
Kaymak E, Farley BM, Hay SA, Li C, Ho S, Hartman DJ, Ryder SP. Efficient generation of transgenic reporter strains and analysis of expression patterns in Caenorhabditis elegans using library MosSCI. Developmental dynamics. 2016; 245(9):925-36. PMID: 27294288, PMCID: PMC4981527
Elewa A, Shirayama M, Kaymak E, Harrison PF, Powell DR, Du Z, Chute CD, Woolf H, Yi D, Ishidate T, Srinivasan J, Bao Z, Beilharz TH, Ryder SP, Mello CC. POS-1 Promotes Endo-mesoderm Development by Inhibiting the Cytoplasmic Polyadenylation of neg-1 mRNA. Developmental Cell. 2015; 34(1):108-18. PMID: 26096734, PMCID: PMC4507413
Kaymak E, Ryder SP. RNA recognition by the Caenorhabditis elegans oocyte maturation determinant OMA-1. The Journal of biological chemistry. 2013; 288(42):30463-72. PMID: 24014033, PMCID: PMC3798510
Post-transcriptional regulation of myelin formation
In the vertebrate central nervous system, myelin is formed by specialized glial cells termed oligodendrocytes. The highly polarized nature of oligodendrocytes, together with the requirement that they sense and respond accurately to their extracellular environment, necessitates the development of strategies to control gene expression at regions distal to the cell body. These strategies influence how the cell decides where to migrate, when to stop dividing and differentiate, and which axons to myelinate. We are studying RNA-binding proteins that contribute to oligodendrocyte differentiation and myelination.
Zearfoss NR, Deveau LM, Clingman CC, Schmidt E, Johnson ES, Massi F, Ryder SP. A conserved three-nucleotide core motif defines Musashi RNA binding specificity. The Journal of biological chemistry. 2014; 289(51):35530-41. PMID: 25368328, PMCID: PMC4271237
Zearfoss NR, Johnson ES, Ryder SP. hnRNP A1 and secondary structure coordinate alternative splicing of Mag. RNA. 2013; 19(7):948-57. PMID: 23704325, PMCID: PMC3683929
Screening for small molecule inhibitors of RNA binding proteins
Small molecule inhibitors can serve as research tools to aid in the study of factors with multiple activities. In addition, for proteins with disease relevance, small molecule inhibitors can provide a starting point for the development of new therapies. We are developing assay pipelines to screen for small molecule inhibitors of RNA-binding proteins involved in cell fate specification events, with an emphasis on protein-metabolite interactions.
Clingman CC, Deveau LM, Hay SA, Genga RM, Shandilya SM, Massi F, Ryder SP. Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite. eLife. 2014; 3. PMID: 24935936, PMCID: PMC4094780
Clingman CC, Ryder SP. Metabolite sensing in eukaryotic mRNA biology. Wiley interdisciplinary reviews. RNA. 2013; 4(4):387-96. PMID: 23653333, PMCID: PMC5026232