Transgenerational Epigenetic Inheritance Is Negatively Regulated by the HERI-1 Chromodomain Protein

Abstract

Transgenerational epigenetic inheritance (TEI) is the inheritance of epigenetic information for two or more generations. In most cases, TEI is limited to a small number of generations (two to three). The short-term nature of TEI could be set by innate biochemical limitations to TEI or by genetically encoded systems that actively limit TEI. In Caenorhabditis elegans, double-stranded RNA (dsRNA)-mediated gene silencing [RNAi (RNA interference)] can be inherited (termed RNAi inheritance or RNA-directed TEI). To identify systems that might actively limit RNA-directed TEI, we conducted a forward genetic screen for factors whose mutation enhanced RNAi inheritance. This screen identified the gene heritable enhancer of RNAi (heri-1), whose mutation causes RNAi inheritance to last longer (. 20 generations) than normal. heri-1 encodes a protein with a chromodomain, and a kinase homology domain that is expressed in germ cells and localizes to nuclei. In C. elegans, a nuclear branch of the RNAi pathway [termed the nuclear RNAi or NRDE (nuclear RNA defective) pathway] promotes RNAi inheritance. We find that heri-1(2) animals have defects in spermatogenesis that are suppressible by mutations in the nuclear RNAi Argonaute (Ago) HRDE-1, suggesting that HERI-1 might normally act in sperm progenitor cells to limit nuclear RNAi and/or RNAi inheritance. Consistent with this idea, we find that the NRDE nuclear RNAi pathway is hyperresponsive to experimental RNAi treatments in heri-1 mutant animals. Interestingly, HERI-1 binds to genes targeted by RNAi, suggesting that HERI-1 may have a direct role in limiting nuclear RNAi and, therefore, RNAi inheritance. Finally, the recruitment of HERI-1 to chromatin depends upon the same factors that drive cotranscriptional gene silencing, suggesting that the generational perdurance of RNAi inheritance in C. elegans may be set by competing pro-and antisilencing outputs of the nuclear RNAi machinery.

Recovery from transgenerational RNA silencing is driven by gene-specific homeostasis

“…4d, Extended Data Fig. 10e), albeit to a much lesser extent than reported in previous cases 40,41 . Similarly, removal of the endonuclease ERI-1 42 weakly increased the persistence of silencing (Extended Data Fig.…”

Emerging Roles for Chromo Domain Proteins in Genome Organization and Cell Fate in C. elegans

“…CD, chromo domain; CSD, chromo shadow domain; ChIP, chromatin immunoprecipitation; in vitro, in vitro peptide binding assay; co-IP, co-immunoprecipitation; Tg, transgene; DB, DELTA-BLAST. ‡ HPL-1, HPL-2: (Couteau et al, 2002;Schott et al, 2006;Koester-Eiserfunke and Fischle, 2011;Studencka et al, 2012a,b;Towbin et al, 2012;Garrigues et al, 2015;Vandamme et al, 2015;McMurchy et al, 2017); CEC-1: (Agostoni et al, 1996;Saltzman et al, 2018); CEC-3: (Greer et al, 2014); CEC-4: (Gonzalez-Sandoval et al, 2015); CEC-6: (Saltzman et al, 2018); HERI-1: (Perales et al, 2018); MRG-1: (Takasaki et al, 2007;Cabianca et al, 2019;Hajduskova et al, 2019).…”

“…In a genetic screen for factors that prolong the transgenerational retention of RNAi inheritance, a recent study characterized the chromo domain protein HERI-1 (heritable enhancer of RNAi; formerly known as CEC-9) (Perales et al, 2018). Interestingly, ChIP assays revealed recruitment of HERI-1 to genes undergoing nuclear RNAi; this recruitment is dependent on HRDE-1 and SET-32 (also known as HRDE-3), a methyltransferase contributing to H3K9 methylation and nuclear RNAi inheritance.…”

“…It will be of great interest to identify the endogenous targets of HERI-1. Additional intriguing mechanistic questions include whether its chromo domain directly interacts with methylated histones, and the potential function of its serinethreonine kinase-like domain as an allosteric regulator or scaffold (Perales et al, 2018). While much attention has been directed to the factors required for RNAi inheritance, HERI-1 joins a handful of genes or environmental perturbations identified so far that restrict TEI (Houri-Ze'evi et al, 2016;Lev et al, 2017).…”

Three Rules Explain Transgenerational Small RNA Inheritance inC. elegans

“…It has been shown that selection enables maintenance of heritable RNAi indefinitely (>80 generations) [10]. Control over the duration of transgenerational silencing is achieved via an elaborate regulatory pathway [8], and disabling some of the genes in the pathway (for example, met-2, which encodes for an H3K9 methyltransferase) leads to stable inheritance [14,25,26]. Currently, the source of variability in the inheritance capacity of genetically identical individuals is completely unaccounted for.…”