Transcription restores DNA repair to heterochromatin, Determining regional mutation rates in cancer genomes
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ABSTRACT:
PROVIDER: PRJNA266683 | ENA |
REPOSITORIES: ENA
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Project description:Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.
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Project description:Transcription restores DNA repair to heterochromatin, Determining regional mutation rates in cancer genomes
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Project description:How heterochromatin genes evolve as ‘gene islands’ to fit into the repressive chromatin environment in plants are poorly understood. To address this question, we performed a comprehensive epigenetic profiling in the genus Oryza with high quality BAC-assembled regional sequences and near gap-free genomes. Comparative analyses of a heterochromatin knob demonstrated the dynamics of chromatin states (heterochromatin versus euchromatin) among the Oryza species in a phylogenetic context. LTR (long-terminal repeat) retrotransposons are the main contributor (~99%) to heterochromatin diversity. Heterochromatin genes are distributed as ‘gene islands’ in heterochromatin, but heterochromatin hardly projects expression disturbance to them. Heterochromatin genes are almost free of H3K9me2 histone modifications in exons, and have similar gene structure and transposon invasion rate in introns to its orthologous euchromatin counterparts. Analyses of the rice HiC data verified the topological existence of ‘gene islands’ and demonstrated that ‘gene islands’ are less spatially co-localized with heterochromatin. By examining evolutionarily recent inserted genes in the Oryza species, we found that the active promoters of six inserted genes can elevate CHH (H=A, C, T) methylation at the insertion sites. Our results reveals that heterochromatin genes evolve as heterochromatin-insulated ‘gene islands’ to escape the repressive influence of heterochromatin, contrasting to the ‘integration’ model in Drosophila. We suggest that active gene promoters may contribute to this insulation by acting as an important heterochromatin-euchromatin boundary in plants.
2020-12-02 | GSE126436 | GEO
Project description:How heterochromatin genes evolve as ‘gene islands’ to fit into the repressive chromatin environment in plants are poorly understood. To address this question, we performed a comprehensive epigenetic profiling in the genus Oryza with high quality BAC-assembled regional sequences and near gap-free genomes. Comparative analyses of a heterochromatin knob demonstrated the dynamics of chromatin states (heterochromatin versus euchromatin) among the Oryza species in a phylogenetic context. LTR (long-terminal repeat) retrotransposons are the main contributor (~99%) to heterochromatin diversity. Heterochromatin genes are distributed as ‘gene islands’ in heterochromatin, but heterochromatin hardly projects expression disturbance to them. Heterochromatin genes are almost free of H3K9me2 histone modifications in exons, and have similar gene structure and transposon invasion rate in introns to its orthologous euchromatin counterparts. Analyses of the rice HiC data verified the topological existence of ‘gene islands’ and demonstrated that ‘gene islands’ are less spatially co-localized with heterochromatin. By examining evolutionarily recent inserted genes in the Oryza species, we found that the active promoters of six inserted genes can elevate CHH (H=A, C, T) methylation at the insertion sites. Our results reveals that heterochromatin genes evolve as heterochromatin-insulated ‘gene islands’ to escape the repressive influence of heterochromatin, contrasting to the ‘integration’ model in Drosophila. We suggest that active gene promoters may contribute to this insulation by acting as an important heterochromatin-euchromatin boundary in plants.
2020-12-02 | GSE126432 | GEO
Project description:How heterochromatin genes evolve as ‘gene islands’ to fit into the repressive chromatin environment in plants are poorly understood. To address this question, we performed a comprehensive epigenetic profiling in the genus Oryza with high quality BAC-assembled regional sequences and near gap-free genomes. Comparative analyses of a heterochromatin knob demonstrated the dynamics of chromatin states (heterochromatin versus euchromatin) among the Oryza species in a phylogenetic context. LTR (long-terminal repeat) retrotransposons are the main contributor (~99%) to heterochromatin diversity. Heterochromatin genes are distributed as ‘gene islands’ in heterochromatin, but heterochromatin hardly projects expression disturbance to them. Heterochromatin genes are almost free of H3K9me2 histone modifications in exons, and have similar gene structure and transposon invasion rate in introns to its orthologous euchromatin counterparts. Analyses of the rice HiC data verified the topological existence of ‘gene islands’ and demonstrated that ‘gene islands’ are less spatially co-localized with heterochromatin. By examining evolutionarily recent inserted genes in the Oryza species, we found that the active promoters of six inserted genes can elevate CHH (H=A, C, T) methylation at the insertion sites. Our results reveals that heterochromatin genes evolve as heterochromatin-insulated ‘gene islands’ to escape the repressive influence of heterochromatin, contrasting to the ‘integration’ model in Drosophila. We suggest that active gene promoters may contribute to this insulation by acting as an important heterochromatin-euchromatin boundary in plants.
2020-12-02 | GSE126431 | GEO
Project description:How heterochromatin genes evolve as ‘gene islands’ to fit into the repressive chromatin environment in plants are poorly understood. To address this question, we performed a comprehensive epigenetic profiling in the genus Oryza with high quality BAC-assembled regional sequences and near gap-free genomes. Comparative analyses of a heterochromatin knob demonstrated the dynamics of chromatin states (heterochromatin versus euchromatin) among the Oryza species in a phylogenetic context. LTR (long-terminal repeat) retrotransposons are the main contributor (~99%) to heterochromatin diversity. Heterochromatin genes are distributed as ‘gene islands’ in heterochromatin, but heterochromatin hardly projects expression disturbance to them. Heterochromatin genes are almost free of H3K9me2 histone modifications in exons, and have similar gene structure and transposon invasion rate in introns to its orthologous euchromatin counterparts. Analyses of the rice HiC data verified the topological existence of ‘gene islands’ and demonstrated that ‘gene islands’ are less spatially co-localized with heterochromatin. By examining evolutionarily recent inserted genes in the Oryza species, we found that the active promoters of six inserted genes can elevate CHH (H=A, C, T) methylation at the insertion sites. Our results reveals that heterochromatin genes evolve as heterochromatin-insulated ‘gene islands’ to escape the repressive influence of heterochromatin, contrasting to the ‘integration’ model in Drosophila. We suggest that active gene promoters may contribute to this insulation by acting as an important heterochromatin-euchromatin boundary in plants.
2020-12-02 | GSE127665 | GEO
Project description:Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, reverses DNA methylation age and counteracts the expression of senescence-associated genes. Moreover, proteome profiling involved in senescence phenotype was partially restored upon depletion of LINE-1 RNA in both Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome (WRN-/-).
2022-11-02 | PXD032944 | Pride
Project description:Evolution of heterochromatin and heterochromatin genes in the Oryza genomes reveals a new heterochromatin-euchromatin boundary
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