Fatty acid (FA) uptake and altered metabolism constitute hallmarks of metastasis 1-2 yet it is unclear the biology behind it, or whether all dietary FAs are prometastatic. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma. Unexpectedly, tumours from mice fed a short-term palm oil (PA)-rich diet, or tumour cells briefly exposed to PA in vitro, remain highly metastatic even when serially transplanted (without further exposure to high levels of PA). This PAinduced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A/COMPASS. Bulk, single-cell and positional RNA sequencing indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumour Schwann cells and innervation, two parameters strongly correlated with metastasis but etiologically poorly understood 3-4 . Mechanistically, tumour-associated Schwann cells secrete a specialized pro-regenerative extracellular matrix, whose ablation inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial cellstimulating peptide galanin. In sum, we provide evidence that a dietary metabolite provokes stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a pro-regenerative state of tumour-activated Schwann cells.
The COMPASS protein family catalyzes histone H3 lysine 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells (mESCs) and found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, recruitment of DNA demethylation machineries on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4me3 underlies transcriptional regulation on MLL2/COMPASS targets.
Set1A and Set1B, two members of the COMPASS family of methyltransferases that methylate the histone H3 lysine 4 (H3K4) residue, have been accredited as primary depositors of global H3K4 trimethylation (H3K4me3) in mammalian cells. Our previous studies in mouse embryonic stem cells (ESCs) demonstrated that deleting the enzymatic SET domain of Set1A does not perturb bulk H3K4me3, indicating possible compensatory roles played by other COMPASS methyltransferases. Here, we generated a series of ESC lines harboring compounding mutations of COMPASS methyltransferases. We find that Set1B is functionally redundant to Set1A in implementing H3K4me3 at highly expressed genes, while Mll2 deposits H3K4me3 at less transcriptionally active promoters. While Set1A-B/COMPASS is responsible for broad H3K4me3 peaks, Mll2/COMPASS establishes H3K4me3 with narrow breadth. Additionally, Mll2 helps preserve global H3K4me3 levels and peak breadth in the absence of Set1A-B activity. Our results illustrate the biological flexibility of such enzymes in regulating transcription in a context-dependent manner to maintain stem cell identity.
Edited by Patrick Sung 5-Aminoimidazole-4-carboxamide 1--D-ribofuranoside (AICAR, or acadesine) is a precursor of the monophosphate derivative 5-amino-4-imidazole carboxamide ribonucleoside 5-phosphate (ZMP), an intermediate in de novo purine biosynthesis. AICAR proved to have promising anti-proliferative properties, although the molecular basis of its toxicity is poorly understood. To exert cytotoxicity, AICAR needs to be metabolized, but the AICAR-derived toxic metabolite was not identified. Here, we show that ZMP is the major toxic derivative of AICAR in yeast and establish that its metabolization to succinyl-ZMP, ZDP, or ZTP (di-and triphosphate derivatives of AICAR) strongly reduced its toxicity. Affinity chromatography identified 74 ZMPbinding proteins, including 41 that were found neither as AMP nor as AICAR or succinyl-ZMP binders. Overexpression of karyopherin- Kap123, one of the ZMP-specific binders, partially rescued AICAR toxicity. Quantitative proteomic analyses revealed 57 proteins significantly less abundant on nuclei-enriched fractions from AICAR-fed cells, this effect being compensated by overexpression of KAP123 for 15 of them. These results reveal nuclear protein trafficking as a function affected by AICAR.
Significance Pluripotency and development can be governed at the level of epigenetics. Growing lines of evidence underscore the importance of the Set1A/complex of proteins associated with SET1 (COMPASS) histone 3 lysine 4 methyltransferase complex in embryogenesis and neurodevelopment. We show that the catalytic SET domain of Set1A is essential for mouse embryogenesis; however, having this domain extends the viability of embryos compared to complete loss of Set1A. We additionally show that Ing5, a core component of several complexes involved in histone acetylation, can functionally interact with Set1A ΔSET in regulating ESC viability and developmental gene expression. Insights into their physiological activity and regulation will assist our understanding of their dysfunction in disease and ultimately facilitate the discovery of new targets for future therapy.
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