Mobile RNA and transgenerational epigenetic inheritance
We are interested in the mechanisms of intercellular RNA transport that support systemic RNAi in C. elegans and extracellular RNA biogenesis and uptake in mice. We are also exploring how these activities enable transgenerational epigenetic inheritance (TEI) and possibly whether TEI may enable organisms to adapt rapidly to environmental change.
A remarkable property of RNA interference (RNAi) in C. elegans is its association with intercellular RNA transport pathways. This linkage mobilizes dsRNA-silencing signals, which enables silencing to spread from the site of initiation throughout the animal and to the progeny. This phenomenon, known as systemic RNAi, is a conserved process among many multicellular organisms. Through genetic analysis, we have isolated systemic RNAi defective mutants (sid) and have identified the corresponding proteins (SID). Among them is SID-1, a widely conserved dsRNA channel that selectively and specifically transports dsRNA into cells. SID-1 is essential for systemic RNAi in nematodes and we have shown that the mammalian SID-1 homolog mediates viral dsRNA import to trigger interferon-mediated antiviral resistance. These findings indicate that dsRNA transport is a conserved function for this family of channel proteins. We continue to investigate the activity, specificity, and regulation of SID-1 in C. elegans as well as the function of the mammalian homologs.
Transgenerational epigenetic inheritance
Siblings resemble each other more than expected based on the genes that they inherit from their parents. This unexpected finding derives from recent studies that measure the association between genotype (variations in DNA sequence) and traits (e.g. height or disease risk) among large populations of unrelated people. These studies show less genotype-trait association than expected. This expectation is based on comprehensive measures of heritability that are calculated from analysis of siblings, including identical twins. This discrepancy indicates that parents may transmit extra, non-gene, information to their offspring. This non-gene information is called epigenetics, literally “beyond” genetics, and is a well-established field, but convention accepts that epigenetic information is largely erased each generation. Recent studies are challenging this convention. An additional provocative and long-disputed thesis is that parental adaptations to local environmental conditions can be transmitted by TEI to their offspring. Evidence for inheritance of these “acquired traits” is apparent in human epidemiological studies (e.g. the Dutch hunger) and is emerging from experiments with laboratory organisms, including from our lab. However, little is known about how inherited epigenetic information is encoded, how it responds to environmental conditions, and how it is transmitted between generations. Because inherited epigenetic information is malleable and may account for up to half the inheritance of disease risk, the answers to these questions will have an enormous impact on society and medicine.
Investigating how TEI is established, maintained, and transmitted is challenging: it requires analysis of multiple generations and studies to date indicate that its effects are impermanent, fading with successive generations. Research in the Hunter lab uses the nematode C. elegans to investigate TEI. C. elegans has numerous experimental advantages for studying TEI, primary among them is a fast generation time and RNAi. Published studies from the Hunter lab show that RNAi-dependent epigenetic silencing can be maintained for nearly 20 generations. This persistent silencing allows detailed molecular genetic analysis on how information is transmitted between generations and whether TEI may enable organisms to adapt to environmental change.
Stable heritable germline silencing directs somatic silencing at an endogenous locus. Minkina O, Hunter CP. Mol Cell. 2017 65(4):659-670.e5. doi:10.1016/j.molcel.2017.01.034. PMID: 28212751
SIDT2 transports extracellular dsRNA into the cytoplasm for innate immune recognition. Nguyen TA et al., Immunity. 2017 47(3):498-509.e6. doi: 10.1016/j.immuni.2017.08.007. PMID: 28916264.
SID-1 functions in multiple roles to support parental RNAi in Caenorhabditis elegans. Wang E, Hunter CP. Genetics. 2017 207(2):547-557. doi: 10.1534/genetics.117.300067. Epub 2017 Jul 27. PMID: 28751423.
SID-1 domains important for dsRNA import in Caenorhabditis elegans. Whangbo JS, Weisman AS, Chae J, Hunter CP. G3. 2017 7(12):3887-3899. doi:10.1534/g3.117.300308. PMID: 29025917.
Early developmental exposure to dsRNA Is critical for initiating efficient nuclear RNAi in C. elegans. Shiu PK, Hunter CP. Cell Rep. 2017 18(12):2969-2978. doi: 10.1016/j.celrep.2017.03.002. PMID: 28329688;
Natural RNA interference directs a heritable response to the environment. Schott D, Yanai I, Hunter CP. Sci Rep. 2014 4:7387. doi: 10.1038/srep07387. PMID: 25552271
The DEAD box helicase RDE-12 promotes amplification of RNAi in cytoplasmic foci in C. elegans. Yang H, Vallandingham J, Shiu P, Li H, Hunter CP, Mak HY. Curr Biol. 2014 24(8):832-8. doi: 10.1016/j.cub.2014.01.008. PMID: 24684930
The nuclear argonaute NRDE-3 contributes to transitive RNAi in Caenorhabditis elegans. Zhuang JJ, Banse SA, Hunter CP. Genetics. 2013 194(1):117-31. doi: 10.1534/genetics.113.149765. PMID: 23457236
SID-5 is an endosome-associated protein required for efficient systemic RNAi in C. elegans. Hinas A, Wright AJ, Hunter CP. Curr Biol. 2012 22(20):1938-43. doi: 10.1016/j.cub.2012.08.020. PMID: 22981770
Conserved tyrosine kinase promotes the import of silencing RNA into Caenorhabditis elegans cells. Jose AM, Kim YA, Leal-Ekman S, Hunter CP. Proc Natl Acad Sci U S A. 2012 109(36):14520-5. doi: 10.1073/pnas.1201153109. PMID: 22912399
Uptake of extracellular double-stranded RNA by SID-2. McEwan DL, Weisman AS, Hunter CP. Mol Cell. 2012 47(5):746-54. doi: 10.1016/j.molcel.2012.07.014. PMID: 22902558
Vampiric isolation of extracellular fluid from Caenorhabditis elegans. Banse SA, Hunter CP. J Vis Exp. 2012 (61). pii: 3647. doi: 10.3791/3647. PMID: 22453516
SID-1 is a dsRNA-selective dsRNA-gated channel. Shih JD, Hunter CP. RNA. 2011 17(6):1057-65. doi: 10.1261/rna.2596511. PMID: 21474576
Caenorhabditis elegans SID-2 is required for environmental RNA interference. Winston WM, Sutherlin M, Wright AJ, Feinberg EH, Hunter CP. Proc Natl Acad Sci U S A. 2007 104(25):10565-70. PMID: 17563372
An antiviral role for the RNA interference machinery in Caenorhabditis elegans. Schott DH, Cureton DK, Whelan SP, Hunter CP. Proc Natl Acad Sci U S A. 2005 102(51):18420-4. PMID: 16339901
Transport of dsRNA into cells by the transmembrane protein SID-1. Feinberg EH, Hunter CP. Science. 2003 301(5639):1545-7. PMID: 12970568
Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Winston WM, Molodowitch C, Hunter CP. Science. 2002 95(5564):2456-9. PMID: 11834782
Intergenerational Transmission of Gene Regulatory Information in Caenorhabditis elegans. Minkina O, Hunter CP. Trends Genet. 2018 34(1):54-64. doi: 10.1016/j.tig.2017.09.012. PMID: 29103876.
RNA interference in Caenorhabditis elegans: uptake, mechanism, and regulation. Zhuang JJ, Hunter CP. Parasitology. 2012 139(5):560-73. doi: 10.1017/S0031182011001788. Review. PMID: 22075748
Environmental RNA interference. Whangbo JS, Hunter CP. Trends Genet. 2008 24(6):297-305. doi: 10.1016/j.tig.2008.03.007. Review. PMID: 18450316
Transport of sequence-specific RNA interference information between cells. Jose AM, Hunter CP. Annu Rev Genet. 2007 41:305-30. Review. PMID: 17645412
Genetics: a touch of elegance with RNAi. Hunter CP. Curr Biol. 1999 9(12):R440-2. Review. PMID: 10375522