RESEARCH HIGHLIGHTS
EPIGENETICS
H3K27 methylation in transgenerational epigenetic memory
NPG
During reproduction, organisms must pass on genomes with suitable epigenetic states to the next generation. These states must be appropriate for gene expression programmes in the progeny and can be ‘reset’ to prevent the unwanted transgenerational inheritance of environmentally induced epigenetic states. Identifying the key molecular players in this epigenetic control is of great interest, and two new studies in worms and plants characterize a key role for histone H3 lysine 27 trimethylation (H3K27me3) in transgenerational epigenetic inheritance. Gaydos et al. studied the inheritance of epigenetic states of X chromosomes in Caenorhabditis elegans. In both sexes of this species, silenced X chromosomes are a characteristic feature of germline identity and development (except during a transient period in late oogenesis). As the H3K27me3 mark is repressive and is ‘written’ by the Polycomb repressive complex 2 (PRC2) histone methyltransferase in various species, the authors investigated the contributions of this histone mark and the enzyme complex to the epigenetic state of the single X chromosome inherited by male worms, as well as the implications for subsequent germline development. Interestingly, in PRC2-deficient males, those that inherited their X chromosome maternally (in an unsilenced state) had germline defects and were typically sterile, whereas those that inherited it paternally (in a silenced state) were generally fertile. Thus, a deficiency for PRC2 could be overcome if the X chromosome was contributed to the embryo
in a silenced state by the sperm, and the authors showed that these sperm from PRC2-deficient parents use a back-up mode of repression involving H3K9me2. In further experiments Gaydos et al. visualized the fates of various H3K27me3-marked chromosomes from oocytes and sperm through mitoses in the resultant embryos. They found that, in the absence of PRC2, H3K27me3 was transmitted to daughter chromosomes through a few cell divisions, but that long-term propagation of H3K27me3 required PRC2. In both cases, H3K27me3 remained restricted to the daughter chromosomes derived from the initially marked parental chromosomes, providing evidence for transmission of epigenetic ‘memory’. In a separate study, Crevillén et al. used Arabidopsis thaliana to study vernalization, the process by which prolonged exposure to cold during the winter is required for the subsequent initiation of flowering in the spring. Vernalization involves cold-mediated epigenetic silencing of the FLOWERING LOCUS C (FLC) gene by Polycomb proteins. Normally, FLC is efficiently reset to a transcriptionally active state during embryogenesis to ensure a requirement for vernalization in every generation. To identify genes that are involved in this resetting, the authors carried out a forward genetic screen on mutagenized plants and isolated mutants that were defective at re-expressing an engineered FLC–luciferase fusion reporter gene in early development. Studying one mutant line in detail through crossing strategies,
NATURE REVIEWS | GENETICS
Crevillén et al. used genetic marker analysis and whole-genome sequencing to track which mutations co-segregated with the mutant phenotype. They pinpointed an Ala→Val mutation in the ELF6 gene as the likely causal lesion and validated this through the rescue of the normal resetting phenotype in mutant plants when a wild-type ELF6 transgene was expressed. Based on its sequence, ELF6 is a likely H3K27 demethylase; consistent with this activity, the authors found that mutant ELF6 resulted in increased levels of H3K27me3 and reduced transcription at the FLC locus in seed capsules (which were used as a proxy for embryos during development). Additionally, mutant ELF6 impaired transcriptional induction of additional FLC-family member genes. Thus, the removal (resetting) of repressive H3K27me3 marks at particular loci during embryogenesis seems to be key for the normal erasure of vernalization memory. Overall, despite distinct biological systems and research questions, both studies highlight a key role for H3K27me3 in the transgenerational inheritance of repressed epigenetic states, with roles in both physiologically normal silencing (for C. elegans X chromosomes) and inappropriate silencing (for the FLC locus in A. thaliana mutants).
Darren J. Burgess
ORIGINAL RESEARCH PAPERS Gaydos, L. J., Wang, W. & Strome, S. H3K27me and PRC2 transmit a memory of repression across generations and during development. Science 345, 1515–1518 (2014) | Crevillén, P. et al. Epigenetic reprogramming that prevents transgenerational inheritance of the vernalized state. Nature http:// dx.doi.org/10.1038/nature13722 (2014)
VOLUME 15 | NOVEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
EPIGENETICS
H3K27 methylation in transgenerational epigenetic memory
NPG
During reproduction, organisms must pass on genomes with suitable epigenetic states to the next generation. These states must be appropriate for gene expression programmes in the progeny and can be ‘reset’ to prevent the unwanted transgenerational inheritance of environmentally induced epigenetic states. Identifying the key molecular players in this epigenetic control is of great interest, and two new studies in worms and plants characterize a key role for histone H3 lysine 27 trimethylation (H3K27me3) in transgenerational epigenetic inheritance. Gaydos et al. studied the inheritance of epigenetic states of X chromosomes in Caenorhabditis elegans. In both sexes of this species, silenced X chromosomes are a characteristic feature of germline identity and development (except during a transient period in late oogenesis). As the H3K27me3 mark is repressive and is ‘written’ by the Polycomb repressive complex 2 (PRC2) histone methyltransferase in various species, the authors investigated the contributions of this histone mark and the enzyme complex to the epigenetic state of the single X chromosome inherited by male worms, as well as the implications for subsequent germline development. Interestingly, in PRC2-deficient males, those that inherited their X chromosome maternally (in an unsilenced state) had germline defects and were typically sterile, whereas those that inherited it paternally (in a silenced state) were generally fertile. Thus, a deficiency for PRC2 could be overcome if the X chromosome was contributed to the embryo
in a silenced state by the sperm, and the authors showed that these sperm from PRC2-deficient parents use a back-up mode of repression involving H3K9me2. In further experiments Gaydos et al. visualized the fates of various H3K27me3-marked chromosomes from oocytes and sperm through mitoses in the resultant embryos. They found that, in the absence of PRC2, H3K27me3 was transmitted to daughter chromosomes through a few cell divisions, but that long-term propagation of H3K27me3 required PRC2. In both cases, H3K27me3 remained restricted to the daughter chromosomes derived from the initially marked parental chromosomes, providing evidence for transmission of epigenetic ‘memory’. In a separate study, Crevillén et al. used Arabidopsis thaliana to study vernalization, the process by which prolonged exposure to cold during the winter is required for the subsequent initiation of flowering in the spring. Vernalization involves cold-mediated epigenetic silencing of the FLOWERING LOCUS C (FLC) gene by Polycomb proteins. Normally, FLC is efficiently reset to a transcriptionally active state during embryogenesis to ensure a requirement for vernalization in every generation. To identify genes that are involved in this resetting, the authors carried out a forward genetic screen on mutagenized plants and isolated mutants that were defective at re-expressing an engineered FLC–luciferase fusion reporter gene in early development. Studying one mutant line in detail through crossing strategies,
NATURE REVIEWS | GENETICS
Crevillén et al. used genetic marker analysis and whole-genome sequencing to track which mutations co-segregated with the mutant phenotype. They pinpointed an Ala→Val mutation in the ELF6 gene as the likely causal lesion and validated this through the rescue of the normal resetting phenotype in mutant plants when a wild-type ELF6 transgene was expressed. Based on its sequence, ELF6 is a likely H3K27 demethylase; consistent with this activity, the authors found that mutant ELF6 resulted in increased levels of H3K27me3 and reduced transcription at the FLC locus in seed capsules (which were used as a proxy for embryos during development). Additionally, mutant ELF6 impaired transcriptional induction of additional FLC-family member genes. Thus, the removal (resetting) of repressive H3K27me3 marks at particular loci during embryogenesis seems to be key for the normal erasure of vernalization memory. Overall, despite distinct biological systems and research questions, both studies highlight a key role for H3K27me3 in the transgenerational inheritance of repressed epigenetic states, with roles in both physiologically normal silencing (for C. elegans X chromosomes) and inappropriate silencing (for the FLC locus in A. thaliana mutants).
Darren J. Burgess
ORIGINAL RESEARCH PAPERS Gaydos, L. J., Wang, W. & Strome, S. H3K27me and PRC2 transmit a memory of repression across generations and during development. Science 345, 1515–1518 (2014) | Crevillén, P. et al. Epigenetic reprogramming that prevents transgenerational inheritance of the vernalized state. Nature http:// dx.doi.org/10.1038/nature13722 (2014)
VOLUME 15 | NOVEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
