Repressive H3K9me2 protects lifespan against the transgenerational burden of COMPASS activity in C. elegans

Lee, Teresa W.; David, Heidi Shira; Engstrom, Amanda; Carpenter, Brandon S.; Katz, David J.

doi:10.7554/elife.48498

Cited by 43 publications

(37 citation statements)

References 46 publications

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“…Rather, loss of H3K4me3 may indirectly affect chromatin structure, and hence transcription on the X. Consistent with such a model, inactivation of SET1/COMPASS subunits results in global changes in repressive H3K9 methylation in both yeast and worms (Robert et al, 2014;Lee et al, 2019;Greenstein et al, 2020) and alters chromatin organization [(Herbette et al, 2017) (see text footnote 1)].…”

Section: Discussionmentioning

confidence: 77%

Caenorhabditis elegans SET1/COMPASS Maintains Germline Identity by Preventing Transcriptional Deregulation Across Generations

Robert

Knutson

Rechtsteiner

et al. 2020

Front. Cell Dev. Biol.

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Chromatin regulators contribute to the maintenance of the germline transcriptional program. In the absence of SET-2, the Caenorhabditis elegans homolog of the SET1/COMPASS H3 Lys4 (H3K4) methyltransferase, animals show transgenerational loss of germline identity, leading to sterility. To identify transcriptional signatures associated with progressive loss of fertility, we performed expression profiling of set-2 mutant germlines across generations. We identify a subset of genes whose misexpression is first observed in early generations, a step we refer to as priming; their misexpression then further progresses in late generations, as animals reach sterility. Analysis of misregulated genes shows that down-regulation of germline genes, expression of somatic transcriptional programs, and desilencing of the X-chromosome are concurrent events leading to loss of germline identity in both early and late generations. Upregulation of transcription factor LIN-15B, the C/EBP homolog CEBP-1, and TGF-β pathway components strongly contribute to loss of fertility, and RNAi inactivation of cebp-1 and TGF-β/Smad signaling delays the onset of sterility, showing they individually contribute to maintenance of germ cell identity. Our approach therefore identifies genes and pathways whose misexpression actively contributes to the loss of germ cell fate. More generally, our data shows how loss of a chromatin regulator in one generation leads to transcriptional changes that are amplified over subsequent generations, ultimately leading to loss of appropriate cell fate.

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Section: Discussionmentioning

confidence: 77%

Caenorhabditis elegans SET1/COMPASS Maintains Germline Identity by Preventing Transcriptional Deregulation Across Generations

Robert

Knutson

Rechtsteiner

et al. 2020

Front. Cell Dev. Biol.

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“…Interestingly, Lee et al [45] recently reported that elevated levels of H3K9me2 at specific regions are associated with longer lifespan. Comparing their H3K9me2 profiles from mixed stage worms revealed a strong statistically significant overlap between the regions that showed age-dependent gain in H3K9me3 in our glp-1 mutant data with the H3K9me2 enriched regions in the long-lived strains (S8B Fig).…”

Section: Resultsmentioning

confidence: 99%

Locus-specific H3K9me3 gain in aged somatic tissues in Caenorhabditis elegans

Wang

et al. 2021

Preprint

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Epigenetic alterations occur as organisms age, and lead to chromatin deterioration, loss of transcriptional silencing and genomic instability. Dysregulated epigenome has been linked to increased susceptibility to age-related disorders. We aim to characterize the age-dependent changes of the epigenome and, in turn, to understand epigenetic processes that drive aging phenotypes. In this study, we focused on the aging-associated changes in the repressive histone marks H3K9me3 and H3K27me3 in C. elegans . We observed redistribution of of both histone marks, but the changes are more significant for H3K9me3. We further found alteration of heterochromatic boundaries in aged somatic tissues. Interestingly, we discovered that the most significant changes reflected H3K9me3-marked regions that are formed during aging, and are absent in developing worms, which we termed “aging-associated repressive domains” (AARDs). These AARDs preferentially occur in genic regions that are marked by high levels of H3K9me2 and H3K36me2 in larval stages. Interestingly, maintenance of high H3K9me2 levels in these regions have been shown to correlate with longer lifespan. Next, we examined whether the changes in repressive histone marks lead to de-silencing of repetitive DNA elements, as reported for several other organisms. We observed increased expression of active repetitive DNA elements but not global re-activation of silent repeats in old worms, likely due to the distributed nature of repetitive elements in the C. elegans genome. Intriguingly, CELE45, a putative short interspersed nuclear elements (SINE), was greatly overexpressed at old age and upon heat stress. SINEs have been suggested to regulate transcription in response to various cellular stresses in mammals, it is likely that CELE45 RNAs also play roles in stress response and aging in C. elegans . Taken together, our study revealed significant and specific age-dependent changes in repressive histone modifications and repetitive elements, providing important insights into aging biology.

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“…Furthermore, the transgenerational inheritance of repressive histone modifications occurs in C. elegans mutants lacking the COMPASS complex component, WDR-5. wdr-5 mutants transgenerationally extend lifespan due to the accumulation of H3K9me2 across generations (Greer et al, 2010;Lee et al, 2019). Histone methylation may also be transmitted across generations in vertebrates (Brykczynska et al, 2010;Hammoud et al, 2009;Wu et al, 2011;Zheng et al, 2016;Zhu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

CoREST has a conserved role in facilitating SPR-5/LSD1 maternal reprogramming of histone methylation

Carpenter¹,

Scott²,

Goldin

et al. 2021

Preprint

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Maternal reprogramming of histone methylation is critical for reestablishing totipotency in the zygote, but how histone modifying enzymes are regulated during maternal reprogramming is not well characterized. To address this gap, we asked whether maternal reprogramming by the H3K4me1/2 demethylase SPR-5/LSD1/KDM1A, is regulated by the co-repressor protein, SPR-1/CoREST in C. elegans and mice. In C. elegans, SPR-5 functions as part of a reprogramming switch together with the H3K9 methyltransferase MET-2. By examining germline development, fertility and gene expression in double mutants between spr-1 and met-2, we find that spr-1 mutants are partially compromised for spr-5; met-2 reprogramming. In mice, we generated a separation of function Lsd1 M448V point mutation that compromises CoREST binding, but only slightly affects LSD1 demethylase activity. When maternal LSD1 in the oocyte is derived exclusively from this allele, the progeny phenocopy the increased perinatal lethality that we previously observed when LSD1 was reduced maternally. Together, these data are consistent with CoREST having a conserved function in facilitating maternal LSD1 epigenetic reprogramming.

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Repressive H3K9me2 protects lifespan against the transgenerational burden of COMPASS activity in C. elegans

Cited by 43 publications

References 46 publications

Caenorhabditis elegans SET1/COMPASS Maintains Germline Identity by Preventing Transcriptional Deregulation Across Generations

Caenorhabditis elegans SET1/COMPASS Maintains Germline Identity by Preventing Transcriptional Deregulation Across Generations

Locus-specific H3K9me3 gain in aged somatic tissues in Caenorhabditis elegans

CoREST has a conserved role in facilitating SPR-5/LSD1 maternal reprogramming of histone methylation

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