Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease

The chromatin landscape of the moss <em>Physcomitrella patens</em> and its dynamics during development and drought stress

International audienceThe moss Physcomitrella patens is an important model organism for evo-devo studies. Here, we determined the genome-wide chromatin landscape of five important histone three (H3) modifications (H3K4me3, H3K27me3, H3K27Ac, H3K9Ac and H3K9me2) and describe the changes to these histone marks in two contrasted situations, developmental transition and abiotic (drought) stress. Integrative analysis of these histone H3 modifications revealed their preferential association into 15 chromatin states (CS) in genic regions of the P. patens genome. Synergistic relationships that influence expression levels were revealed for the three activating marks H3K4me3, H3K27Ac and H3K9Ac, while an antagonistic relationship was found between CS containing the H3K27me3 and H3K27Ac marks, suggesting that H3K27 is a key indexing residue regarding transcriptional output. Concerning the alteration of histone marks in response to developmental transition (juvenile to adult) and drought stress, the three activating marks H3K4me3, H3K27Ac and H3K9Ac show significant changes in both situations. However, changes to H3K27me3 are central only for genes differentially expressed during development. Interestingly, genes induced during drought stress show significant histone mark toggling during developmental transition. This situation suggests that drought induced adult (gametophore expressed) genes are primed to respond to this stress during the juvenile to adult transition

epiAneufinder identifies copy number alterations from single-cell ATAC-seq data

Abstract Single-cell open chromatin profiling via scATAC-seq has become a mainstream measurement of open chromatin in single-cells. Here we present epiAneufinder, an algorithm that exploits the read count information from scATAC-seq data to extract genome-wide copy number alterations (CNAs) for individual cells, allowing the study of CNA heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show that epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNA profiles. We demonstrate that these profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. EpiAneufinder allows the inference of single-cell CNA information from scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored

GO annotation of R40 transcripts

GO annotation of R40 transcript

Predicted ORFs for the R40 transcripts

Predicted ORFs for the R40 transcripts. We selected the longest ORF prediction for each transcript

De novo assembly and comparative analysis of the Ceratodon purpureus transcriptome

The bryophytes are a morphologically and ecologically diverse group of plants that have recently emerged as major model systems for a variety of biological processes. In particular, the genome sequence of the moss, Physcomitrella patens, has significantly enhanced our understanding of the evolution of developmental processes in land plants. However, to fully explore the diversity within bryophytes, we need additional genomic resources. Here, we describe analyses of the transcriptomes of a male and a female isolate of the moss, Ceratodon purpureus, generated using the 454 FLX technology. Comparative analyses between C. purpureus and P. patens indicated that this strategy generated nearly complete coverage of the protonemal transcriptome. An analysis of the overlap in gene sets between C. purpureus and P. patens provides new insights into the evolution of gene family composition across the land plants. In spite of the overall transcriptomic similarity between the two species, Ka/Ks analysis of P. patens and C. purpureus suggests considerable physiological and developmental divergence. Additionally, while the codon usage was very similar between these two mosses, C. purpureus genes showed a slightly greater codon usage bias than P. patens genes potentially because of the contrasting mating system of the two species. Finally, we found evidence of a genome doubling ~65–76 MYA that likely coincided with the contemporaneous polyploidy event inferred for P. patens but postdates the divergence of P. patens and C. purpureus. The powerful laboratory tools now available for C. purpureus will enable the research community to fully exploit these genomic resources

Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging

The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging

BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis

Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to “remember” time in the absence of external cues

Assembled R40 transcripts

We assembled quality filtered and trimmed 454 reads with Newbler for the R40 strain

Predicted ORFs for the GG1 transcripts

Predicted ORFs for the GG1 transcripts. We selected the longest ORF prediction for each transcript