Abstract
Transcription of protein coding genes is accompanied by recruitment of COMPASS to promoter-proximal chromatin, which methylates histone H3 lysine 4 (H3K4) to form H3K4me1, H3K4me2 and H3K4me3. Here, we determine the importance of COMPASS in maintaining gene expression across lifespan in budding yeast. We find that COMPASS mutations reduce replicative lifespan and cause expression defects in almost 500 genes. Although H3K4 methylation is reported to act primarily in gene repression, particularly in yeast, repressive functions are progressively lost with age while hundreds of genes become dependent on H3K4me3 for full expression. Basal and inducible expression of these genes is also impaired in young cells lacking COMPASS components Swd1 or Spp1. Gene induction during ageing is associated with increasing promoter H3K4me3, but H3K4me3 also accumulates in non-promoter regions and the ribosomal DNA. Our results provide clear evidence that H3K4me3 is required to maintain normal expression of many genes across organismal lifespan.
Highlights
H3K4me3 is ubiquitously observed on nucleosomes at the 5’ end of eukaryotic genes undergoing active transcription by RNA polymerase II
A published micromanipulation screen of 264 yeast mutants found that cells lacking COMPASS components Swd1 or Swd3 have replicative lifespans ~ 20% shorter than wild type (Smith et al, 2008)
Replicative lifespan measures the number of times a mother cell can divide before losing viability, compared to chronological lifespan which measures the time for which cells remain viable irrespective of cell division
Summary
H3K4me is ubiquitously observed on nucleosomes at the 5’ end of eukaryotic genes undergoing active transcription by RNA polymerase II (see for example [Barski et al, 2007; Bernstein et al, 2005; Liu et al, 2005; Zhang et al, 2009]). Budding yeast has a single COMPASS complex containing the catalytic SET-domain protein Set and core structural proteins Swd and Swd, along with Sdc, Bre, Swd and Spp (Figure 1A). Swd and Swd are required for all H3K4 methylation activity, while Sdc and Bre are necessary for di- and tri-methylation (Deheet al., 2006; Schneider et al, 2005). Neither Swd nor Spp are required for H3K4 methylation in vitro (Takahashi et al, 2011), but mutation of Swd almost completely abrogates H3K4me and reduces H3K4me in vivo (Cheng et al, 2004; Lee et al, 2007), while loss of Spp dramatically reduces H3K4me in vivo without impacting H3K4me1/2 (Deheet al., 2006; Schneider et al, 2005)
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