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Novel roles of C. elegans heterochromatin protein HP1 and linker histone HIS-24 in the regulation of innate immune gene expression and stress Response

ABSTRACT: Linker histone H1 and heterochromatin protein 1 (HP1) are essential components ofheterochromatin which contribute to the transcriptional repression of genes. It has been shown that the methylation mark on the histone H1 serves as a specific recognition code for the chromodomain of HP1, however, the functional role of the HP1/H1 complex remains elusive. Using C. elegans, we elucidate the function of the linker histone variant HIS-24 and heterochromatin proteins HPL/HP1 in the cooperative transcriptional regulation of immunerelevant and stress resistance genes. We also show that HIS-24 and HPL act redundantly in vulval cell fate specification and gonad development. Finally, we provide the first evidence that HPL-1 interacts with HIS-24 at mono-methylated lysine 14 and associates in vivo with promoters of infection-inducible genes: the caenacin (cnc)- and the thaumatin (thn)- gene clusters. Our results highlight a functional link between epigenetic regulation by HP1/H1 the innate immune system and stress response.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE25714 | GEO | 2011/11/28

SECONDARY ACCESSION(S): PRJNA133837

REPOSITORIES: GEO

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Project description:Parental exposure to environmental stress can result in an increased diseases risk in the offspring. Although literature on maternal contribution to hereditary diseases are growing, the paternal contribution is frequently underrecognized. Since human studies reported that 80% of transmitted mutations arise in the paternal germline, it is crucial to understand the mechanism underlying the paternally inherited genome instability. Ionizing radiation (IR) is a major source of mutagenesis through inducing DNA double-strand breaks (DSBs). Here, we used sex-separated C. elegans mutants to investigate the paternal contribution to IR-induced transgenerational effects. Specifically, we found that paternal exposure to IR leads to a transgenerational embryonic lethality, and this effect is only observed when the radiation exposure occurred close to the time of fertilization. In the offspring of the irradiated males (F1 generation), we detected various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement, and aneuploidy. These phenotypes are attributed to the usage of two error-prone repair machinery, the polymerase-theta mediated end joining (TMEJ) and the non-homologous End Joining (NHEJ). Surprisingly, depletion of a human histone H1.0 ortholog, HIS-24, can significantly rescue this transgenerational embryonic lethality. Moreover, this rescue effect is associated with the downregulation of heterochromatin marker histone 3 lysine 9 di-methylation (H3K9me2), and the knocking-down of heterochromatin protein, HPL-1, could mimic the rescue effect of HIS-24 depletion. We also noticed that removal of the histone H1 and heterochromatin marker could activate the error-free repair machinery, Homologous Recombination repair (HR), thus improving the viability of the offspring carrying paternally inherited DNA damage. Altogether, our work sheds light on the importance of paternal radiation exposure on the health of offspring. In addition, our work establishes a previously unknown mechanism underlying the transgenerational genome instability and provides a potential therapeutic target for preventing the hereditary diseases caused by paternal radiation exposure.

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Novel roles of C. elegans heterochromatin protein HP1 and linker histone HIS-24 in the regulation of innate immune gene expression and stress Response

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