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Transcriptional repression of Hox genes by binding of HP1 and methylated H1 to H3K27me3 in C. elegans

ABSTRACT: Elucidation of the biological role of H1 and HP1 in mammals has been difficult owing to the existence of a least 11 distinct H1 and three HP1 subtypes in mice. Therefore we decided to study the function of HP1 (HPL-1 and HPL-2) and H1 (HIS-24) related proteins in C. elegans, since hpls and his-24 deficient nematodes are viable. Global transcriptional analysis of the mutant animals revealed that expression of only a small number of genes was affected and HPLs, and HIS-24 appear to influence the expression of genes through either activation or repression. Interestingly, knockout of HPL-2 and HIS-24 caused chromatin structure changes in the germline without altering core histone modifications. Furthermore, the mutant animals showed abnormal development of the male tail and the ectopic expression of C. elegans HOM-C genes (egl-5 and mab-5) involved in the developmental patterning of the mating structures. Surprisingly, H3K27me3 chromatin mark presented at the C. elegans HOM-C gene promoters was recognized by HPL-2 and methylated form of HIS-24. We propose that methylated HIS-24 and HPL-2 bind independently to PcG target loci that have been trimethylated at H3K27 by C. elegans MES-2 [E(Z)] to transcriptionally repress the Hox genes. Our results establish interplay of the H3K27me3 binding proteins, HP1/HPLs and H1/HIS-24 in the regulation of positional identity in the C. elegans males.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE33339 | GEO | 2012/08/13

SECONDARY ACCESSION(S): PRJNA148965

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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Transcriptional repression of Hox genes by binding of HP1 and methylated H1 to H3K27me3 in C. elegans

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