Tri-methylation of histone H3 lysine 4 facilitates gene expression in ageing cells

Cruz, Cristina; Rosa, Monica Della; Krueger, Christel; Gao, Qian; Horkai, Dorottya; King, Michelle; Field, Lucy; Houseley, Jonathan

doi:10.7554/elife.34081

Cited by 81 publications

(88 citation statements)

References 91 publications

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“…S. cerevisiae has a single COMPASS complex containing the catalytic SET‐domain protein Set1 and core structural proteins Swd1, Swd3, Sdc1, Bre2, Swd2, and Spp1. Consistent with the previous report, Cruz et al found that catalytic‐inactive set1 H1017L , Δ swd1, and Δ spp1 mutant yeast strains exhibit significant RLS defect resulting specifically from loss of H3K4me3 (Cruz et al, ).…”

Section: Methionine Metabolism and Lifespan Extension In Yeastsupporting

confidence: 86%

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

et al. 2019

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Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast, certain cancer cells exhibit methionine auxotrophy that can be exploited for therapeutic treatment, as decreasing dietary methionine selectively suppresses tumor growth. Thus, MetR represents an intervention that can extend lifespan with a complementary effect of delaying tumor growth. Beyond its function in protein synthesis, methionine feeds into complex metabolic pathways including the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Manipulation of each of these branches extends lifespan; however, the interplay between MetR and these branches during regulation of lifespan is not well understood. In addition, a potential mechanism linking the activity of methionine metabolism and lifespan is regulation of production of the methyl donor S‐adenosylmethionine, which, after transferring its methyl group, is converted to S‐adenosylhomocysteine. Methylation regulates a wide range of processes, including those thought to be responsible for lifespan extension by MetR. Although the exact mechanisms of lifespan extension by MetR or methionine metabolism reprogramming are unknown, it may act via reducing the rate of translation, modifying gene expression, inducing a hormetic response, modulating autophagy, or inducing mitochondrial function, antioxidant defense, or other metabolic processes. Here, we review the mechanisms of lifespan extension by MetR and different branches of methionine metabolism in different species and the potential for exploiting the regulation of methyltransferases to delay aging.

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Section: Methionine Metabolism and Lifespan Extension In Yeastsupporting

confidence: 86%

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

et al. 2019

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“…Although the precise biological role of H3K4me3 is unclear, its importance is nevertheless apparent. In S. cerevisiae, loss of Spp1 (and therefore H3K4me3) is linked to poor chronological ageing (Cruz et al, 2018;Walter et al, 2014), while murine Cfp1−/− embryonic stem cells are incapable of differentiating (Carlone and Skalnik, 2001). In humans, chromosomal translocations in SET-containing genes are frequently associated with acute myeloid and lymphoid leukemias (Shilatifard, 2012).…”

Section: Discussionmentioning

confidence: 99%

H3K4me3 is neither instructive for, nor informed by, transcription

Lorenz

et al. 2019

Preprint

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H3K4me3 is a near-universal histone modification found predominantly at the 5' region of genes, with a well-documented association with gene activity. H3K4me3 has been ascribed roles as both an instructor of gene expression and also a downstream consequence of expression, yet neither has been convincingly proven on a genome-wide scale. Here we test these relationships using a combination of bioinformatics, modelling and experimental data from budding yeast in which the levels of H3K4me3 have been massively ablated. We find that loss of H3K4me3 has no effect on the levels of nascent transcription or transcript in the population. Moreover, we observe no change in the rates of transcription initiation, elongation, mRNA export or turnover, or in protein levels, or cell-to-cell variation of mRNA. Loss of H3K4me3 also has no effect on the large changes in gene expression patterns that follow galactose induction. Conversely, loss of RNA polymerase from the nucleus has no effect on the pattern of H3K4me3 deposition and little effect on its levels, despite much larger changes to other chromatin features. Furthermore, large genome-wide changes in transcription, both in response to environmental stress and during metabolic cycling, are not accompanied by corresponding changes in H3K4me3. Thus, despite the correlation between H3K4me3 and gene activity, neither appear to be necessary to maintain levels of the other, nor to influence their changes in response to environmental stimuli. When we compare gene classes with very different levels of H3K4me3 but highly similar transcription levels we find that H3K4me3-marked genes are those whose expression is unresponsive to environmental changes, and that their histones are less acetylated and dynamically turned-over. Constitutive genes are generally well-expressed, which may alone explain the correlation between H3K4me3 and gene expression, while the biological role of H3K4me3 may have more to do with this distinction in gene class.

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“…Cells were incubated for 30 min on a wheel at room temperature, washed once with 100 µl PBS and re-suspended in 100 μl PBS, then inoculated in required media at 2x10 4 cells/ml and allowed to recover for 2 hours at 30° before addition of 1µM β-estradiol (Sigma E2758) and CuSO4 as required. For ageing in YPD or YPGal, the same protocol was followed but no recovery period was included -as previously noted this prevents culture saturation without detectable contamination of young cells by 24-48 hours [31]. Cells were harvested by repeated centrifugation for 1 min, 4600 rpm in 50 ml tubes and immediately fixed by resuspension in 70% ethanol and stored at -80°C.…”

Section: Mep Cell Labelling and Purificationmentioning

confidence: 99%

“…Retention of ERCs in mother cells involves tethering by SAGA and TREX2 to nuclear pore complexes, which are themselves largely retained in mother cells, with mutation of SAGA components abrogating retention and extending mother cell lifespan [28][29][30]. ERCs replicate on each division and mother cell retention leads to exponential copy number amplification, increasing genome size by 50% in 24 hours [31], which is thought to interfere with various critical pathways to accelerate, if not cause, ageing pathology [32,33].…”

Section: Introductionmentioning

confidence: 99%

Transcription-induced formation of extrachromosomal DNA during yeast ageing

Hull

King

Pizza

et al. 2019

Preprint

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Extrachromosomal circular DNA (eccDNA) facilitates adaptive evolution by allowing rapid and extensive gene copy number variation, and is implicated in the pathology of cancer and ageing. Here, we demonstrate that yeast aged under environmental copper accumulate high levels of eccDNA containing the copper resistance gene CUP1. Transcription of CUP1 causes CUP1 eccDNA accumulation, which occurs in the absence of phenotypic selection. We have developed a sensitive and quantitative eccDNA sequencing pipeline that reveals CUP1 eccDNA accumulation on copper exposure to be exquisitely site specific, with no other detectable changes across the eccDNA complement. eccDNA forms de novo from the CUP1 locus through processing of DNA double-strand breaks (DSBs) by Sae2 / Mre11 and Mus81, and genome-wide analyses show that other protein coding eccDNA species in aged yeast share a similar biogenesis pathway. Although abundant we find that CUP1 eccDNA does not replicate efficiently, and high copy numbers in aged cells arise through frequent formation events combined with asymmetric DNA segregation. The transcriptional stimulation of CUP1 eccDNA formation shows that age-linked genetic change varies with transcription pattern, resulting in gene copy number profiles tailored by environment.

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Tri-methylation of histone H3 lysine 4 facilitates gene expression in ageing cells

Cited by 81 publications

References 91 publications

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

H3K4me3 is neither instructive for, nor informed by, transcription

Transcription-induced formation of extrachromosomal DNA during yeast ageing

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