Regulation of gene expression is fundamental to biology, and alterations in gene expression are a frequent cause of human disease. Gene regulation is typically investigated at the level of transcription, yet there is a growing recogniton of consequential post-transcriptional modulation of gene expression. In many eukaryotes, including animals, microRNAs (miRNAs) direct much of post-transcriptional regulation. MicroRNAs are short, non-coding, regulatory RNAs that post-transcriptionally repress gene expression by basepairing to target messenger RNAs (mRNAs). In humans, miRNAs contribute to a wide variety of biological pathways, moreover, mutations perturbing miRNAs, or their targeting, are implicated in a growing number of human diseases, including a variety of forms of cancer. Since their initial discovery, much has been learned about the biogenesis, regulation and mode of action of miRNAs, however, our knowledge is incomplete and the identification of novel factors involved in miRNA biology will help us better understand how these important regulatory molecules function in humans.
Our first aim i s to identify new protein factors involved in miRNA biology;our approach uses RNAi to inhibit each human gene and a novel cell-based screening strategy to identify genes whose inhibition alters miRNA function. In our second aim, we focus on improving our ability to identify the target mRNAs for each miRNA, this remains a fundamental question in miRNA biology, both to better understand the mechanisms of miRNAs as a class, and to understand the biological functions of individual miRNAs. Despite the increasing sophistication in computational approaches to miRNA target prediction, continued progress is limited by the availability of suitable experimental techniques and data to validate and refine models. Because state-of-the-art predictions contain many errors, yet are of great utility and widely-used, we are motivated to design an improved experimental framework for target identification;our method allows the high-throughput assessment of miRNA target sites in a minimally perturbed endogenous cellular environment. The increasingly widespread recognition of the impact of miRNAs on many fields of biology suggests that such efforts could have broad applicability.

Public Health Relevance

MicroRNAs are a large family of small RNA molecules that contribute to the regulation of most mammalian genes. As a result of their large number of regulatory targets, microRNAs play important roles in human development, and mutations that perturb microRNAs or their target interactions contribute to human disease, including cancer. We are using novel methods in mammalian cells to discover proteins required for the function of microRNAs, and, to identify the regulatory targets of microRNAs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cornell University
Schools of Arts and Sciences
United States
Zip Code
Geissler, Rene; Grimson, Andrew (2018) Characterizing mRNA Sequence Motifs in the 3'-UTR Using GFP Reporter Constructs. Methods Mol Biol 1720:77-88
Hilz, Stephanie; Fogarty, Elizabeth A; Modzelewski, Andrew J et al. (2017) Transcriptome profiling of the developing male germ line identifies the miR-29 family as a global regulator during meiosis. RNA Biol 14:219-235
Vo, Tommy V; Das, Jishnu; Meyer, Michael J et al. (2016) A Proteome-wide Fission Yeast Interactome Reveals Network Evolution Principles from Yeasts to Human. Cell 164:310-323
Wissink, Erin M; Fogarty, Elizabeth A; Grimson, Andrew (2016) High-throughput discovery of post-transcriptional cis-regulatory elements. BMC Genomics 17:177
Wang, Jocelyn; Wissink, Erin M; Watson, Neva B et al. (2016) Fetal and adult progenitors give rise to unique populations of CD8+ T cells. Blood 128:3073-3082
Kristjánsdóttir, Katla; Fogarty, Elizabeth A; Grimson, Andrew (2015) Systematic analysis of the Hmga2 3' UTR identifies many independent regulatory sequences and a novel interaction between distal sites. RNA 21:1346-60
Smith, Norah L; Wissink, Erin M; Grimson, Andrew et al. (2015) miR-150 Regulates Differentiation and Cytolytic Effector Function in CD8+ T cells. Sci Rep 5:16399
Wissink, Erin M; Smith, Norah L; Spektor, Roman et al. (2015) MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells. Genetics 201:1017-30
Modzelewski, Andrew J; Hilz, Stephanie; Crate, Elizabeth A et al. (2015) Dgcr8 and Dicer are essential for sex chromosome integrity during meiosis in males. J Cell Sci 128:2314-27
Smith, Norah L; Wissink, Erin; Wang, Jocelyn et al. (2014) Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life. J Immunol 193:177-84