Research Overview
Our lab is interested in gene regulation and genomics, with an emphasis on post-transcriptional gene regulation. A recurring theme in our work is understanding the mechanisms and consequences of regulation of the transcriptome. Current projects range from mechanistic studies of 3ʹuntranslated regions (3ʹUTRs) in mammalian cells, to understanding the gene regulatory networks controlled by microRNAs (miRNAs) in the immune system. Some of our major project areas are described below.
3′UTR Biology
A core part of the lab is focused on identifying and understanding the mechanisms by which 3ʹUTRs control gene expression. Ongoing projects include the development of novel high-throughput assays to dissect 3ʹUTR regulatory pathways. Other projects focus on regulatory outcomes controlled by long 3ʹUTRs.
Representative publications in this area:
Kwak Y, Daly CWP, Fogarty EA, Grimson A*, Kwak H*. Dynamic and widespread control of poly(A) tail length during macrophage activation. RNA. 2022 Jul;28(7):947-971. doi: 10.1261/rna.078918.121. PMID: 35512831.
*Co-corresponding authors
Patel RK, West JD, Jiang Y, Fogarty EA, Grimson A. Robust partitioning of microRNA targets from downstream regulatory changes. Nucleic Acids Res. 2020 Sep 25;48(17):9724-9746. doi: 10.1093/nar/gkaa687. PMID: 32821933.
Simkin A*, Geissler R, McIntyre ABR, Grimson A*. Evolutionary dynamics of
microRNA target sites across vertebrate evolution. PLoS Genet. 2020 Feb
3;16(2):e1008285. doi: 10.1371/journal.pgen.1008285. PMID: 32012152.
*Co-corresponding authors
MiRNAs in the Immune System
In collaboration with Brian Rudd, Cornell University
We use the mammalian immune system (T cells) as a model to study miRNA biology in vivo. In particular, we have found two miRNAs, miR-29 and let-7, that act as master regulators of CD8+ T cells: both of these miRNAs are essential to immune memory function. Newborns express miR-29 and let-7 at lowered levels and therefore lack robust CD8+ T cell memory functionality, in addition to other important differences with the adult immune system. Current projects include understanding the gene regulatory network controlled by let-7 and miR-29 in mouse and human cells, and understanding the physiological consequences of natural variation in levels of these miRNAs. In addition, we are interested in exploring differences in the adult and newborn immune systems.
Representative publications in this area:
Yee Mon KJ, Zhu H, Daly CWP, Vu LT, Smith NL, Patel R, Topham DJ, Scheible K, Jambo K, Le MTN, Rudd BD*, Grimson A*. MicroRNA-29 specifies age-related differences in the CD8+ T cell immune response. Cell Rep. 2021 Nov 9;37(6):109969. doi: 10.1016/j.celrep.2021.109969. PMID: 34758312.
*Co-corresponding authors
Smith NL, Patel RK, Reynaldi A, Grenier JK, Wang J, Watson NB, Nzingha K, Yee Mon KJ, Peng SA, Grimson A, Davenport MP, Rudd BD. Developmental Origin Governs CD8(+) T Cell Fate Decisions during Infection. Cell. 2018 Jun 28;174(1):117-130.e14. doi: 10.1016/j.cell.2018.05.029.
Wang J, Wissink EM, Watson NB, Smith NL, Grimson A*, Rudd BD*. Fetal and adult progenitors give rise to unique populations of CD8+ T cells. Blood. 2016 Dec 29;128(26):3073-3082. doi: 10.1182/blood-2016-06-725366.
*Co-corresponding authors
Wissink EM, Smith NL, Spektor R, Rudd BD*, Grimson A*. MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells. Genetics. 2015 Nov;201(3):1017-30. doi: 10.1534/genetics.115.179176.
*Co-corresponding authors
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS)
In collaboration with Maureen Hanson, Cornell University
ME/CFS is a prevalent, often serious, and remarkably poorly understood human disease. Dysregulation of the immune system is a consequence and potential cause of ME/CFS; however, our understanding of the role and importance of the immune system in ME/CFS is in its infancy. We lead one of the three core projects that together comprise the Cornell ME/CFS Center, a recently funded NIH initiative. Our approach is to exploit genomic tools to systematically examine gene dysregulation across the immune system in ME/CFS patients, with the initial goal of identifying specific factors and pathways that are altered in patients.
Small RNAs in the Male Germline
In collaboration with Paula Cohen, Cornell University.
Gene regulation in the male germline is remarkably diverse. In particular, multiple small RNA pathways play core roles, which are required for normal germline function, and ultimately, fertility. In addition to canonical roles for miRNAs, we are also interested in understanding noncanonical small RNA pathways in the germline.
Representative publications in this area:
Hilz S, Fogarty EA, Modzelewski AJ, Cohen PE, Grimson A. Transcriptome profiling of the developing male germ line identifies the miR-29 family as a global regulator during meiosis. RNA Biol. 2017 Feb;14(2):219-235. doi: 10.1080/15476286.2016.1270002.
Modzelewski AJ, Hilz S, Crate EA, Schweidenback CT, Fogarty EA, Grenier JK, Freire R, Cohen PE*, Grimson A*. Dgcr8 and Dicer are essential for sex chromosome integrity during meiosis in males. J Cell Sci. 2015 Jun 15;128(12):2314-27. doi: 10.1242/jcs.167148.
*Co-corresponding authors
Modzelewski AJ, Holmes RJ, Hilz S, Grimson A*, Cohen PE*. AGO4 regulates entry into meiosis and influences silencing of sex chromosomes in the male mouse germline. Dev Cell. 2012 Aug 14;23(2):251-64. doi: 10.1016/j.devcel.2012.07.003.
*Co-corresponding authors