Lexiang Ji

BACKGROUND: DNA methylation is an important feature of plant epigenomes, involved in the formation of heterochromatin and affecting gene expression. Extensive variation of DNA methylation patterns within a species has been uncovered from studies of natural variation. However, the extent to which DNA methylation varies between flowering plant species is still unclear. To understand the variation in genomic patterning of DNA methylation across flowering plant species, we compared single base resolution DNA methylomes of 34 diverse angiosperm species. RESULTS: By analyzing whole-genome bisulfite sequencing data in a phylogenetic context, it becomes clear that there is extensive variation throughout angiosperms in gene body DNA methylation, euchromatic silencing of transposons and repeats, as well as silencing of heterochromatic transposons. The Brassicaceae have reduced CHG methylation levels and also reduced or loss of CG gene body methylation. The Poaceae are characterized by a lack or reduction of heterochromatic CHH methylation and enrichment of CHH methylation in genic regions. Furthermore, low levels of CHH methylation are observed in a number of species, especially in clonally propagated species. CONCLUSIONS: These results reveal the extent of variation in DNA methylation in angiosperms and show that DNA methylation patterns are broadly a reflection of the evolutionary and life histories of plant species.

Significance DNA methylation in plants is found at CG, CHG, and CHH sequence contexts. In plants, CG DNA methylation is enriched in the transcribed regions of many constitutively expressed genes (gene body methylation; gbM) and shows correlations with several chromatin modifications. Contrary to other types of DNA methylation, the evolution and function of gbM are largely unknown. Here we show two independent concomitant losses of the DNA methyltransferase CHROMOMETHYLASE 3 (CMT3) and gbM without the predicted disruption of transcription and of modifications to chromatin. This result suggests that CMT3 is required for the establishment of gbM in actively transcribed genes, and that gbM is dispensable for normal transcription as well as for the composition and modification of plant chromatin.

Abstract Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems 1–5 . Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)—one such nociceptor-produced neuropeptide—directly increases the exhaustion of cytotoxic CD8 + T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8 + T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8 + T cells, Ramp1 −/ − CD8 + T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1 -deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1 -expressing CD8 + T cells were more exhausted than their RAMP1 -negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8 + T cells.

Recent studies have shown that one of the parental subgenomes in ancient polyploids is generally more dominant, having retained more genes and being more highly expressed, a phenomenon termed subgenome dominance. The genomic features that determine how quickly and which subgenome dominates within a newly formed polyploid remain poorly understood. To investigate the rate of emergence of subgenome dominance, we examined gene expression, gene methylation, and transposable element (TE) methylation in a natural, <140-year-old allopolyploid (Mimulus peregrinus), a resynthesized interspecies triploid hybrid (M. robertsii), a resynthesized allopolyploid (M. peregrinus), and progenitor species (M. guttatus and M. luteus). We show that subgenome expression dominance occurs instantly following the hybridization of divergent genomes and significantly increases over generations. Additionally, CHH methylation levels are reduced in regions near genes and within TEs in the first-generation hybrid, intermediate in the resynthesized allopolyploid, and are repatterned differently between the dominant and recessive subgenomes in the natural allopolyploid. Subgenome differences in levels of TE methylation mirror the increase in expression bias observed over the generations following hybridization. These findings provide important insights into genomic and epigenomic shock that occurs following hybridization and polyploid events and may also contribute to uncovering the mechanistic basis of heterosis and subgenome dominance.