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. 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 erased each generation. Studies in the emerging field of transgenerational epigenetic inheritance (TEI) are challenging this convention. 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. The proposed research uses the nematode C. elegans to investigate TEI. C. elegans has numerous experimental advantages for studying TEI, primary among them is a fast, three-day, generation time and a powerful molecular tool called RNA interference (RNAi), which can direct the silencing of any gene. One special characteristic of RNAi in C. elegans is that the silencing signals, a form of RNA, can move between cells and tissues, including to the germline, thus transmitting silencing to future generations. Published studies from the applicants group characterized an RNAi-dependent mechanism of TEI, showing that epigenetic silencing could be maintained for nearly 20 generations. To further explore the transmission of TEI in C. elegans the applicant proposes (Aim 1) to investigate the activity and selectivity of proteins that transport RNA between cells;
(Aim 2) to characterize the biogenesis and transport of endogenous mobile RNAs and to investigate their role in epigenetic inheritance;
and (Aim 3) to investigate the prevalence, mechanisms, and utility of TEI for organismal adaption to environmental change.

Public Health Relevance

This research project uses a model organism to discover and characterize how gene-specific information is shared between cells and generations to regulate genes and inherited traits. The finding could have implications for understanding how disease risk runs in families and how new biomarker test are interpreted.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089795-10
Application #
9744715
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
2009-09-30
Project End
2022-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Minkina, Olga; Hunter, Craig P (2018) Intergenerational Transmission of Gene Regulatory Information in Caenorhabditis elegans. Trends Genet 34:54-64
Whangbo, Jennifer S; Weisman, Alexandra S; Chae, Jeiwook et al. (2017) SID-1 Domains Important for dsRNA Import in Caenorhabditis elegans. G3 (Bethesda) 7:3887-3899
Minkina, Olga; Hunter, Craig P (2017) Stable Heritable Germline Silencing Directs Somatic Silencing at an Endogenous Locus. Mol Cell 65:659-670.e5
Wang, Eddie; Hunter, Craig P (2017) SID-1 Functions in Multiple Roles To Support Parental RNAi in Caenorhabditis elegans. Genetics 207:547-557
Shiu, Philip K; Hunter, Craig P (2017) Early Developmental Exposure to dsRNA Is Critical for Initiating Efficient Nuclear RNAi in C. elegans. Cell Rep 18:2969-2978
Nguyen, Tan A; Smith, Blake R C; Tate, Michelle D et al. (2017) SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition. Immunity 47:498-509.e6
Yang, Huan; Vallandingham, Jim; Shiu, Philip et al. (2014) The DEAD box helicase RDE-12 promotes amplification of RNAi in cytoplasmic foci in C. elegans. Curr Biol 24:832-8
Schott, Daniel; Yanai, Itai; Hunter, Craig P (2014) Natural RNA interference directs a heritable response to the environment. Sci Rep 4:7387
Shiu, Philip K; Zhuang, Jimmy J; Hunter, Craig P (2014) Assays for direct and indirect effects of C. elegans endo-siRNAs. Methods Mol Biol 1173:71-87
Zhuang, Jimmy J; Banse, Stephen A; Hunter, Craig P (2013) The nuclear argonaute NRDE-3 contributes to transitive RNAi in Caenorhabditis elegans. Genetics 194:117-31

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