Andrew Grimson is an Assistant Professor in the Department of Molecular biology & Genetics. He received a B.A. in Genetics at Trinity College Dublin(Ireland) in 1997, and a Ph.D. in Genetics at the University of Wisconsin-Madison in 2004. As a graduate student he worked on the genetics and the biochemistry of nonsense-mediated mRNA decay, a eukaryotic mRNA decay pathway. In 2004, he joined the Bartel laboratory at the Whitehead Institute for Biomedical Research as a National Institutes of Health Postdoctoral Fellow. His postdoctoral research focused on microRNA-mediated (miRNA) regulation of target mRNAs and the early evolution of miRNAs in animals. He joined the Cornell faculty in 2009.
The Grimson lab focuses on post-transcriptional gene regulation, in particular the identity and function of animal microRNAs and other small RNAs, as well as explorations into novel regulatory functions encoded in the 3' untranslated region (3'UTR).. To address these research areas, we use a combination of approaches, including molecular biology, high-throughput genome-scale datasets (e.g., high-throughput sequencing, microarrays), and computational biology/bioinformatics analysis.
MicroRNAs (miRNAs, ~22 nt endogenous RNAs), which function as post-transcriptional negative regulators of gene expression, play a pervasive and significant role in a variety of biological processes, including development and cancer. While the list of miRNA-regulated biological pathways is steadily growing, our appreciation of the breadth and significance of miRNAs to the regulation of gene expression remains in its early stages. About half of mammalian genes possess conserved miRNA binding/target site sequences within their 3'-UTRs (Lewis et al., 2005), and the prediction of mRNA targets continues to improve (e.g., Grimson et al. 2007). However, the vast majority of miRNA/target interactions have not been studied and current prediction algorithms are imperfect and omit obvious parameters (e.g., cooperative and combinatorial action of sites, influence of miRNA abundance). One focus of the Grimson lab is to further refine our ability to predict miRNA target genes, including combinatorial regulation of targets by multiple miRNAs.
While miRNAs have been well characterized in model organisms such as mice, flies, and worms, and a related but independently evolved lineage of miRNAs are found in plants, little is known about the evolutionary origins of animal small RNAs and their protein machinery. The study of basal animals, those that diverged prior to the emergence of Bilateria, thus promises to illuminate the early evolution of animal miRNAs and their ancestral functions. Previous work demonstrated that the small RNA protein machinery and a variety of small RNAs (including miRNAs) existed in the last common metazoan ancestor (Grimson et al., 2008). The Grimson lab will continue to explore small RNA evolution and function in basal animals and in single-celled relatives of Metazoans.
Novel modes of 3′UTR regulation
Biological complexity derives, in part, from the regulation of transcriptional activity of genes and from myriad protein-based signaling events that ensue. However, it is becoming increasingly clear that post-transcriptional gene regulation also contributes significantly to biology. In addition to miRNAs, a variety of other post-transcriptional regulatory mechanisms operate via the 3'UTR of mRNAs. In fact, several recent investigations highlight the 3′UTR as harboring much of the information cells use to govern post-transcriptional fate. A seminal pilot study of C. elegans genes found that 3′UTRs were often sufficient to confer transgenes with the same expression pattern as the gene the 3′UTR was derived from (Merritt et al. 2008). Furthermore, as mammalian cells differentiate, there are global shifts in 3′UTR definition (Sandberg et al. 2008), resulting in different 3′UTR sequences (and thereby different regulatory information) for the same gene. Underscoring the likely abundance of 3'UTR-encoded information, comparative genomics readily identifies many conserved sequence elements in 3′UTRs – the majority of which have no known function (e.g., Xie et al. 2005). A major focus of the Grimson lab is to investigate 3′UTR sequence elements and the underlying mechanisms that respond to such elements.
A new study from Andrew Grimson's lab, in collaboration with Paula Cohen's lab, has identified a key pathway required for maintenance of sex chromosome telomere integrity. Using conditional knockout mice for Dicer and Dgcr8, two key enzymes required for small RNA processing, Modzelewski et al (2015) show that loss of small RNAs during prophase I leads to telomere fusion events specifically involving the X and Y chromosomes. For further information, see the May edition of Journal of Cell Science
A recent publication by Dabaja et al (2015) has identified key cell:cell interactions that are necessary to establish normal profiles of one key microRNA, miR202-5p, in Sertoli cells. This is the first example of a germ cell regulatory interaction that is necessary for miR expression in neighboring somatic cells of the testis
The lab of Center member John Schimenti recently identified the DNA damage checkpoint pathway responsible for culling oocytes that fail to repair double stranded breaks (DSBs) that occur during meiosis or which arise in a female's oocyte pool (Bolcun-Filas et al, Science 343:533-536, 2014). Using combinations of mutants involved in recombination and DNA damage responses, they found that this pathway involves signaling of checkpoint kinase 2 (CHK2) to both p53 and p63. Disruption of this checkpoint pathway restored fertility to females that normally would be deficient of all oocytes due to defects in meiotic recombination or exposure to radiation. This discovery opens the way to using available CHK2 inhibitors to protect the oocytes of women undergoing cancer therapy that would normally cause infertility.