Impaired histone inheritance promotes tumor progression
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ABSTRACT:
PROVIDER: PRJNA830520 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we constructed a tumor model of impaired inheritance of parental histones by introducing an MCM2 histone-binding domain (HBD) mutation in the breast cancer cell lines MCF-7. In this model, impaired histone inheritance resulted in dramatic epigenetic reprogramming, especially the pattern of the repressive histone mark H3K27me3, and promoted tumor growth and metastasis in vivo.
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Project description:Chromatin-based epigenetic memory relies on the accurate distribution of parental histone tetramers to newly replicated DNA strands, serving as templates for chromatin structure duplication. Mcm2, a subunit of the replicative helicase, and the Dpb3/4, subunits of polymerase epsilon, govern parental histone deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here we show in fission yeast that a Mcm2 histone chaperone mutation severely disrupts heterochromatin inheritance, while Dpb3/4 mutations cause only moderate defects. Surprisingly, simultaneous Mcm2 and Dpb3/4 mutations stabilizes heterochromatin inheritance. eSPAN analyses confirm the conservation of Mcm2 and Dpb3/4 functions in parental histone segregation, with their collective absence reducing segregation bias. Furthermore, the FACT histone chaperone also regulates parental histone transfer independently of strands and collaborates with Mcm2 and Dpb3/4 to maintain parental histone density, ensuring faithful heterochromatin inheritance. These results underscore the importance of precise parental histone segregation to the lagging strand for epigenetic inheritance and unveil unique properties of parental histone chaperones during DNA replication.
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Project description:Faithful transfer of parental histones to newly replicated daughter DNA strands is critical for inheritance of epigenetic states. Although replication proteins that facilitate parental histone transfer have been identified, how intact histone H3-H4 tetramers travel relatively large distances from the front to the back of the replication fork remains unknown. Here, we use AlphaFold-Multimer structural predictions combined with biochemical and genetic approaches to identify the Mrc1/CLASPIN subunit of the replisome as a histone chaperone. Mrc1 contains a conserved histone binding domain that forms a brace around the H3-H4 tetramer mimicking nucleosomal DNA and H2A-H2B histones, is required for heterochromatin inheritance, and promotes parental histone recycling during replication. We further identify binding sites for the FACT histone chaperone in Swi1/TIMELESS and DNA polymerase α that are required for heterochromatin inheritance. We propose that Mrc1, in concert with FACT acting as a mobile co-chaperone, coordinates the distribution of parental histones to newly replicated DNA.
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Project description:The transgenerational inheritance of epigenetic information is an attractive mechanism by which the phenotypic consequences of exposure of parents to certain environmental conditions could be transmitted to the next generation. Although this phenomenon is well described in yeast and plants, and in some invertebrates, such as the D. melanogaster and C. elegans, the evidence for transgenerational inheritance in vertebrates is scarce. Among the mechanisms that are known or suspected to be involved in mediating the propagation of epigenetic information to subsequent generations, the process of enzymatic DNA methylation is of particular interest. During DNA replication, the methylation pattern of the parental strand is faithfully copied onto the daughter strand by the maintenance methylase DNMT1, although methylation patterns can be changed through the action of de novo methylases and mechanisms of active and passive demethylation. In the context of epigenetic inheritance, the induction of aberrant methylation patterns in gametes may set the stage for transmission into future generations. Here, we describe a viable hypomorphic allele of dnmt1 in zebrafish that causes widespread demethylation of CpG dinucleotides in sperm and somatic tissues. Surprisingly, homozygous mutants present with an essentially normal phenotype, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. Male but not female mutants are fertile. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by about 50% of fish that are genotypically wildtype. Whole genome bisulfite sequencing of sperm DNA of transmitting and non-transmitting males identified about 200 differentially methylated regions, including hypermethylated sites associated with runx3 and rptor genes. Knock-down of these two genes leads to impaired larval T cell development. Our results raise the possibility of an epigenetic origin of certain immunodeficiency syndromes in animals and humans.
2020-07-07 | GSE98647 | GEO
Project description:Epigenetic Transgenerational Inheritance of Altered Sperm Histone Retention Sites
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Project description:A cytoplasmic Argonaute protein promotes the inheritance of RNAi
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Project description:RNAi-elicited gene silencing is heritable and can persist for multiple generations after its initial induction in C. elegans. However, the mechanism by which parental-acquired trait-specific information from RNAi is inherited by the progenies is not fully understood. Here, we identified a cytoplasmic Argonaute protein, WAGO-4, necessary for the inheritance of RNAi. WAGO-4 exhibits asymmetrical translocation to the germline during early embryogenesis, accumulates at the perinuclear foci in the germline, and is required for the inheritance of exogenous RNAi targeting both germline- and soma-expressed genes. WAGO-4 binds to 22G-RNA and its mRNA targets. Interestingly, WAGO-4-associated endogenous 22G-RNA targets the same cohort of germline genes as CSR-1 and similarly contains untemplated addition of uracil at the 3' ends. The poly(U) polymerase CDE-1 is required for the untemplated polyuridylation of WAGO-4-associated 22G-RNAs and inheritance of RNAi. Therefore, we conclude that the cytoplasmic Argonaute protein WAGO-4 also promotes the inheritance of RNAi in addition to the nuclear RNAi pathway.
2018-04-28 | GSE112475 | GEO