Epigenetics is the study of changes in gene expression or phenotypes that are not the result of changes in DNA sequence. RNA has emerged as an important informational vector directing many epigenetic processes. Additionally, for most of the last century it was widely believed that (unlike genetic information) epigenetic information did not pass across generational boundaries. In other words, epigenetic information was erased each and every generation such that offspring began life with a blank epigenetic slate. It is now known that this is not always the case. Many examples of the trans-generational transfer of epigenetic information have now been documented. The inheritance of epigenetic information for more than one generation is termed transgenerational epigenetic inheritance (TEI). Non-coding RNAs and, in particular, small non-coding RNAs such as piRNAs, miRNAs, siRNAs, and tRNAs have now been linked to TEI in plants, worms, insects, and mammals. Thus, small non-coding RNAs are important informational vectors for TEI in many eukaryotes. In most eukaryotes, dsRNA induces gene silencing (RNAi). We have used RNAi in C. elegans to identify factors that couple small non-coding RNAs to transcriptional regulation. Recently, these studies led us to discover a new type of silencing RNA that we term the pUG RNA. Amazingly, progeny of C. elegans subjected to RNAi inherit the ability to silence RNAi-targeted genes for many (5-10) generations (termed RNAi inheritance). Thus, RNAi inheritance in C. elegans is a particular robust example of RNA-directed TEI. We are also using RNAi inheritance in C. elegans as a model system to explore the mechanistic underpinnings of RNA-directed TEI in animals. We are using genetic screens to identify cellular factors required for promoting and limiting TEI and biochemical and cell biological approaches to explore how these factors drive TEI. Finally, we are also using this system to explore why animals have TEI systems in the first place. The evolutionarily conserved connections between non-coding RNAs and TEI processes in many different species suggests that the work we are doing in C. elegans may lead to fundamental insights into mechanisms of TEI, which will be applicable to eukaryotes in general. The mis-regulation of epigenetic pathways is known to contribute to the etiology of dozens of human diseases, including cancer. Our proposed work will likely increase our understanding of how RNA reprograms epigenetic states and, therefore, may help us understand and, possibly, treat these diseases. Additionally, the question of whether or not people can inherit epigenetic information from their parents is the subject of intense scientific debate. If people can indeed inherit epigenetic information from their parents then it stands to reason they could inherit the wrong epigenetic information, which might predispose to disease. Our work exploring mechanisms of RNA-directed TEI may make it possible to influence TEI pathways in people to mitigate disease.

Public Health Relevance

Non-coding RNAs are important regulators of gene expression programs as well as major vectors for transgenerational epigenetic inheritance. We are using the animal model organism C. elegans to understand the mechanism(s) by which non-coding RNAs mediate these important biological processes. The work we are doing may make it possible to influence gene expression programs and epigenetic inheritance pathways in ways that mitigate human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM088289-10A1
Application #
9732759
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
2009-07-01
Project End
2023-06-30
Budget Start
2019-07-25
Budget End
2020-06-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Perales, Roberto; Pagano, Daniel; Wan, Gang et al. (2018) Transgenerational Epigenetic Inheritance Is Negatively Regulated by the HERI-1 Chromodomain Protein. Genetics 210:1287-1299
Wan, Gang; Fields, Brandon D; Spracklin, George et al. (2018) Spatiotemporal regulation of liquid-like condensates in epigenetic inheritance. Nature 557:679-683
Spracklin, George; Fields, Brandon; Wan, Gang et al. (2017) The RNAi Inheritance Machinery of Caenorhabditis elegans. Genetics 206:1403-1416
Juang, Bi-Tzen; Gu, Chen; Starnes, Linda et al. (2013) Endogenous nuclear RNAi mediates behavioral adaptation to odor. Cell 154:1010-1022
Gu, Sam Guoping; Pak, Julia; Guang, Shouhong et al. (2012) Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint. Nat Genet 44:157-64
Buckley, Bethany A; Burkhart, Kirk B; Gu, Sam Guoping et al. (2012) A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. Nature 489:447-51
Burton, Nick O; Burkhart, Kirk B; Kennedy, Scott (2011) Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans. Proc Natl Acad Sci U S A 108:19683-8
Burkhart, Kirk B; Guang, Shouhong; Buckley, Bethany A et al. (2011) A pre-mRNA-associating factor links endogenous siRNAs to chromatin regulation. PLoS Genet 7:e1002249
Guang, Shouhong; Bochner, Aaron F; Burkhart, Kirk B et al. (2010) Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription. Nature 465:1097-101
Guang, Shouhong; Bochner, Aaron F; Pavelec, Derek M et al. (2008) An Argonaute transports siRNAs from the cytoplasm to the nucleus. Science 321:537-41