Cancer mutational processes vary in their association with replication timing and chromatin accessibility

Regional mutagenesis in cancer genomes associates with DNA replication timing (RT) and chromatin accessibility (CA) of normal cells, however human cancer epigenomes remain uncharacterized in this context. Here we model megabase-scale mutation frequencies in 2517 cancer genomes with 773 CA and RT profiles of cancers and normal cells. We find that CA profiles of matching cancers, rather than normal cells, predict regional mutagenesis and mutational signatures, indicating that most passenger mutations follow the epigenetic landscapes of transformed cells. Carcinogen-induced and unannotated signatures show the strongest associations with epigenomes. Associations with normal cells in melanomas, lymphomas and SBS1 signatures suggest earlier occurrence of mutations in cancer evolution. Frequently mutated regions unexplained by CA and RT are enriched in cancer genes and developmental pathways, reflecting contributions of localized mutagenesis and positive selection. These results underline the complex interplay of mutational processes, genome function and evolution in cancer and tissues of origin.

Download Full-text

Low Replicative Stress Triggers Cell-Type Specific Inheritable Advanced Replication Timing

International Journal of Molecular Sciences ◽

10.3390/ijms22094959 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4959

Author(s):

Lilas Courtot ◽

Elodie Bournique ◽

Chrystelle Maric ◽

Laure Guitton-Sert ◽

Miguel Madrid-Mencía ◽

...

Keyword(s):

Replication Timing ◽

Replication Stress ◽

Chromatin Accessibility ◽

Cell Type ◽

Replicative Stress ◽

Daughter Cells ◽

Origin Activation ◽

Cell Type Specific ◽

Cellular Identity ◽

Dna Replication Timing

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.

Download Full-text

Accessibility Over Transposable Elements Reveals Genetic Determinants of Stemness Properties in Normal and Leukemic Hematopoiesis

10.1101/2021.02.16.431334 ◽

2021 ◽

Author(s):

Bettina Nadorp ◽

Giacomo Grillo ◽

Aditi Qamra ◽

Amanda Mitchell ◽

Christopher Arlidge ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Chromatin Accessibility ◽

Genetic Determinants ◽

Hematopoietic Stem ◽

Transcription Regulators ◽

Docking Sites ◽

Cellular Hierarchy ◽

Mutational Processes

AbstractDespite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two thirds of patients will relapse with fatal disease within 5 years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known of the genetic determinants of their stemness properties 6–8. Although much AML research focuses on mutational processes and their impact on gene expression programs, the genetic determinants of cell state properties including stemness expand beyond mutations, relying on the genetic architecture captured in the chromatin of each cell 9–11. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC), we identified genetic determinants of primitive populations enriched for LSCs and HSCs in comparison with their downstream mature progeny by investigating their chromatin accessibility. Our work reveals how distinct transposable element (TE) subfamilies are used in primitive versus mature populations, functioning as docking sites for stem cell-associated regulators of genome topology, including CTCF, or lineage-specific transcription regulators in primitive and mature populations, respectively. We further show how TE subfamilies accessible in LSCs define docking sites for several oncogenic drivers in AML, namely FLI1, LYL1 and MEIS1. Using chromatin accessibility profiles from a cohort of AML patients, we further show the clinical utility of our TE accessibility-based LSCTE121 scoring scheme to identify patients with high rates of relapse. Collectively, our work reveals how different accessible TE subfamilies serve as genetic determinants of stemness properties in normal and leukemic hematopoietic stem cells.

Download Full-text

Population sequencing data reveal a compendium of mutational processes in the human germ line

Science ◽

10.1126/science.aba7408 ◽

2021 ◽

pp. eaba7408

Author(s):

Vladimir B. Seplyarskiy ◽

Ruslan A. Soldatov ◽

Evan Koch ◽

Ryan J. McGinty ◽

Jakob M. Goldmann ◽

...

Keyword(s):

Germ Line ◽

Nonnegative Matrix ◽

Replication Timing ◽

Mutagenic Effect ◽

Dna Lesions ◽

Sequencing Data ◽

Biological Interpretation ◽

Mutagenic Process ◽

Mutational Processes ◽

Transcription And Replication

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of LINE repeats. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

Download Full-text

Great ape mutation spectra vary across the phylogeny and the genome due to distinct mutational processes that evolve at different rates

10.1101/805598 ◽

2019 ◽

Cited By ~ 1

Author(s):

Michael E. Goldberg ◽

Kelley Harris

Keyword(s):

Replication Timing ◽

Mutation Rates ◽

Great Ape ◽

Mutational Signatures ◽

Clock Model ◽

Cis Acting ◽

Molecular Clock Model ◽

Species Specific ◽

Mutation Spectra ◽

Mutational Processes

ABSTRACTRecent studies of hominoid variation have shown that mutation rates and spectra can evolve rapidly, contradicting the fixed molecular clock model. The relative mutation rates of three-base-pair motifs differ significantly among great ape species, suggesting the action of unknown modifiers of DNA replication fidelity. To illuminate the footprints of these hypothetical mutators, we measured mutation spectra of several functional compartments (such as late-replicating regions) that are likely targeted by localized mutational processes. Using genetic diversity from 88 great apes, we find that compartment-specific mutational signatures appear largely conserved between species. These signatures layer with species-specific signatures to create rich mutational portraits: for example, late-replicating regions in gorillas contain an identifiable mixture of a replication timing signature and a gorilla-specific signature. Our results suggest that cis-acting mutational modifiers are highly conserved between species and transacting modifiers are driving rapid mutation spectrum evolution.

Download Full-text

Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1900714116 ◽

2019 ◽

Vol 116 (36) ◽

pp. 17916-17924 ◽

Cited By ~ 11

Author(s):

Ipsita Agarwal ◽

Molly Przeworski

Keyword(s):

X Chromosome ◽

Rare Variants ◽

Low Frequency ◽

Replication Timing ◽

Double Strand Breaks ◽

X Chromosomes ◽

Strand Breaks ◽

Biochemical Processes ◽

Males And Females ◽

Mutational Processes

The sources of human germline mutations are poorly understood. Part of the difficulty is that mutations occur very rarely, and so direct pedigree-based approaches remain limited in the numbers that they can examine. To address this problem, we consider the spectrum of low-frequency variants in a dataset (Genome Aggregation Database, gnomAD) of 13,860 human X chromosomes and autosomes. X-autosome differences are reflective of germline sex differences and have been used extensively to learn about male versus female mutational processes; what is less appreciated is that they also reflect chromosome-level biochemical features that differ between the X and autosomes. We tease these components apart by comparing the mutation spectrum in multiple genomic compartments on the autosomes and between the X and autosomes. In so doing, we are able to ascribe specific mutation patterns to replication timing and recombination and to identify differences in the types of mutations that accrue in males and females. In particular, we identify C > G as a mutagenic signature of male meiotic double-strand breaks on the X, which may result from late repair. Our results show how biochemical processes of damage and repair in the germline interact with sex-specific life history traits to shape mutation patterns on both the X chromosome and autosomes.

Download Full-text

Chromosomal coordination and differential structure of asynchronous replicating regions

Nature Communications ◽

10.1038/s41467-021-21348-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Britny Blumenfeld ◽

Hagit Masika ◽

Marganit Farago ◽

Yishai Yehuda ◽

Lamia Halaseh ◽

...

Keyword(s):

Population Level ◽

Replication Timing ◽

Gene Families ◽

Chromatin Accessibility ◽

Early Embryogenesis ◽

Epigenetic Mark ◽

Parallel Orientation ◽

Asynchronous Replication ◽

Genome Wide ◽

New Gene

AbstractStochastic asynchronous replication timing (AS-RT) is a phenomenon in which the time of replication of each allele is different, and the identity of the early allele varies between cells. By taking advantage of stable clonal pre-B cell populations derived from C57BL6/Castaneous mice, we have mapped the genome-wide AS-RT loci, independently of genetic differences. These regions are characterized by differential chromatin accessibility, mono-allelic expression and include new gene families involved in specifying cell identity. By combining population level mapping with single cell FISH, our data reveal the existence of a novel regulatory program that coordinates a fixed relationship between AS-RT regions on any given chromosome, with some loci set to replicate in a parallel and others set in the anti-parallel orientation. Our results show that AS-RT is a highly regulated epigenetic mark established during early embryogenesis that may be used for facilitating the programming of mono-allelic choice throughout development.

Download Full-text

Population sequencing data reveal a compendium of mutational processes in human germline

10.1101/2020.01.10.893024 ◽

2020 ◽

Author(s):

Vladimir B. Seplyarskiy ◽

Ruslan A. Soldatov ◽

Ryan J. McGinty ◽

Jakob M. Goldmann ◽

Ryan Hernandez ◽

...

Keyword(s):

Large Scale ◽

Replication Timing ◽

Mutagenic Effect ◽

Dna Lesions ◽

Sequencing Data ◽

Biological Interpretation ◽

Mutagenic Process ◽

Mutational Processes ◽

Transcription And Replication

Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.

Download Full-text

Allele-specific control of replication timing and genome organization during development

10.1101/221762 ◽

2017 ◽

Cited By ~ 2

Author(s):

Juan Carlos Rivera-Mulia ◽

Andrew Dimond ◽

Daniel Vera ◽

Claudia Trevilla-Garcia ◽

Takayo Sasaki ◽

...

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Genome Organization ◽

Replication Timing ◽

Cell Types ◽

Chromatin Accessibility ◽

Parental Origin ◽

F1 Hybrid ◽

Primary Mouse ◽

Allele Specific

AbstractDNA replication occurs in a defined temporal order known as the replication-timing (RT) program. RT is regulated during development in discrete chromosomal units, coordinated with transcriptional activity and 3D genome organization. Here, we derived distinct cell types from F1 hybrid musculus X castaneus mouse crosses and exploited the high single nucleotide polymorphism (SNP) density to characterize allelic differences in RT (Repli-seq), genome organization (Hi-C and promoter-capture Hi-C), gene expression (nuclear RNA-seq) and chromatin accessibility (ATAC-seq). We also presentHARP: a new computational tool for sorting SNPs in phased genomes to efficiently measure allele-specific genome-wide data. Analysis of 6 different hybrid mESC clones with different genomes (C57BL/6, 129/sv and CAST/Ei), parental configurations and gender revealed significant RT asynchrony between alleles across ~12 % of the autosomal genome linked to sub-species genomes but not to parental origin, growth conditions or gender. RT asynchrony in mESCs strongly correlated with changes in Hi-C compartments between alleles but not SNP density, gene expression, imprinting or chromatin accessibility. We then tracked mESC RT asynchronous regions during development by analyzing differentiated cell types including extraembryonic endoderm stem (XEN) cells, 4 male and female primary mouse embryonic fibroblasts (MEFs) and neural precursors (NPCs) differentiatedin vitrofrom mESCs with opposite parental configurations. Surprisingly, we found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs was largely lost in all differentiated cell types, coordinated with a more uniform Hi-C compartment arrangement, suggesting that genome organization of homologues converges to similar folding patterns during cell fate commitment.

Download Full-text

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

10.1101/2020.08.19.256883 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lilas Courtot ◽

Elodie Bournique ◽

Chrystelle Maric ◽

Laure Guitton-Sert ◽

Miguel Madrid-Mencía ◽

...

Keyword(s):

Cancer Cells ◽

Mammalian Cells ◽

Replication Timing ◽

Replication Stress ◽

Chromatin Accessibility ◽

Genome Replication ◽

Origin Activation ◽

Early Replication ◽

Dna Damage Signalling ◽

The Impact

ABSTRACTDNA replication is well orchestrated in mammalian cells through a tight regulation of the temporal order of replication origin activation, named the replication timing, a robust and conserved process in each cell type. Upon low replication stress, the slowing of replication forks induces delayed replication of fragile regions leading to genetic instability. The impact of low replication stress on the replication timing in different cellular backgrounds has not been explored yet. Here we analysed the whole genome replication timing in a panel of 6 human cell lines under low replication stress. We first demonstrated that cancer cells were more impacted than non-tumour cells. Strikingly, we unveiled an enrichment of specific replication domains undergoing a switch from late to early replication in some cancer cells. We found that advances in replication timing correlate with heterochromatin regions poorly sensitive to DNA damage signalling while being subject to an increase of chromatin accessibility. Finally, our data indicate that, following release from replication stress conditions, replication timing advances can be inherited by the next cellular generation, suggesting a new mechanism by which cancer cells would adapt to cellular or environmental stress.

Download Full-text