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

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 (RNA interference)] can be inherited (termed 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 duanyu1615 inheritance. This screen identified the gene heritable enhancer of duanyu1615 (heri-1), whose mutation causes duanyu1615 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 duanyu1615 pathway [termed the nuclear duanyu1615 or NRDE (nuclear RNA defective) pathway] promotes duanyu1615 inheritance. We find that heri-1(-) animals have defects in spermatogenesis that are suppressible by mutations in the nuclear duanyu1615 Argonaute (Ago) HRDE-1, suggesting that HERI-1 might normally act in sperm progenitor cells to limit nuclear duanyu1615 and/or duanyu1615 inheritance. Consistent with this idea, we find that the NRDE nuclear duanyu1615 pathway is hyperresponsive to experimental duanyu1615 treatments in heri-1 mutant animals. Interestingly, HERI-1 binds to genes targeted by suggesting that HERI-1 may have a direct role in limiting nuclear duanyu1615 and, therefore, duanyu1615 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 duanyu1615 inheritance in C. elegans may be set by competing pro- and antisilencing outputs of the nuclear duanyu1615 machinery.

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