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1. Gametes deficient for Pot1 telomere binding proteins alter levels of telomeric foci for multiple generations

   https://doi.org/10.1038/s42003-020-01624-7  

   Lister-Shimauchi, Evan H.; Dinh, Michael; Maddox, Paul; Ahmed, Shawn (February 2021, Communications Biology)

   Abstract Deficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance.C. elegansProtection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes frompot-2mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes frompot-1mutants orpot-1;pot-2double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose thatC. elegansPOT-1 may interact with H3K9 methyltransferases duringpot-2mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci. 

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2. Caenorhabditis elegans establishes germline versus soma by balancing inherited histone methylation

   https://doi.org/10.1242/dev.196600  

   Carpenter, Brandon S.; Lee, Teresa W.; Plott, Caroline F.; Rodriguez, Juan D.; Brockett, Jovan S.; Myrick, Dexter A.; Katz, David J. (February 2021, Development)

   ABSTRACT Formation of a zygote is coupled with extensive epigenetic reprogramming to enable appropriate inheritance of histone methylation and prevent developmental delays. In Caenorhabditis elegans, this reprogramming is mediated by the H3K4me2 demethylase SPR-5 and the H3K9 methyltransferase, MET-2. In contrast, the H3K36 methyltransferase MES-4 maintains H3K36me2/3 at germline genes between generations to facilitate re-establishment of the germline. To determine whether the MES-4 germline inheritance pathway antagonizes spr-5; met-2 reprogramming, we examined the interaction between these two pathways. We found that the developmental delay of spr-5; met-2 mutant progeny is associated with ectopic H3K36me3 and the ectopic expression of MES-4-targeted germline genes in somatic tissues. Furthermore, the developmental delay is dependent upon MES-4 and the H3K4 methyltransferase, SET-2. We propose that MES-4 prevents crucial germline genes from being repressed by antagonizing maternal spr-5; met-2 reprogramming. Thus, the balance of inherited histone modifications is necessary to distinguish germline versus soma and prevent developmental delay. This article has an associated ‘The people behind the papers’ interview. 

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3. Heterochromatin is a quantitative trait associated with spontaneous epiallele formation

   https://doi.org/10.1038/s41467-021-27320-6  

   Zhang, Yinwen; Jang, Hosung; Xiao, Rui; Kakoulidou, Ioanna; Piecyk, Robert S.; Johannes, Frank; Schmitz, Robert J. (December 2021, Nature Communications)

   Abstract Epialleles are meiotically heritable variations in expression states that are independent from changes in DNA sequence. Although they are common in plant genomes, their molecular origins are unknown. Here we show, using mutant and experimental populations, that epialleles in Arabidopsis thaliana that result from ectopic hypermethylation are due to feedback regulation of pathways that primarily function to maintain DNA methylation at heterochromatin. Perturbations to maintenance of heterochromatin methylation leads to feedback regulation of DNA methylation in genes. Using single base resolution methylomes from epigenetic recombinant inbred lines (epiRIL), we show that epiallelic variation is abundant in euchromatin, yet, associates with QTL primarily in heterochromatin regions. Mapping three-dimensional chromatin contacts shows that genes that are hotspots for ectopic hypermethylation have increases in contact frequencies with regions possessing H3K9me2. Altogether, these data show that feedback regulation of pathways that have evolved to maintain heterochromatin silencing leads to the origins of spontaneous hypermethylated epialleles. 

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4. Dynamic evolution of the heterochromatin sensing histone demethylase IBM1

   https://doi.org/10.1371/journal.pgen.1011358  

   Zhang, Yinwen; Jang, Hosung; Luo, Ziliang; Dong, Yinxin; Xu, Yangyang; Kantamneni, Yamini; Schmitz, Robert J (July 2024, PLOS Genetics)

   Mittelsten_Scheid, Ortrun (Ed.)

   Heterochromatin is critical for maintaining genome stability, especially in flowering plants, where it relies on a feedback loop involving the H3K9 methyltransferase, KRYPTONITE (KYP), and the DNA methyltransferase CHROMOMETHYLASE3 (CMT3). The H3K9 demethylase INCREASED IN BONSAI METHYLATION 1 (IBM1) counteracts the detrimental consequences of KYP-CMT3 activity in transcribed genes.IBM1expression inArabidopsisis uniquely regulated by methylation of the 7th intron, allowing it to monitor global H3K9me2 levels. We show the methylated intron is prevalent across flowering plants and its underlying sequence exhibits dynamic evolution. We also find extensive genetic and expression variations inKYP,CMT3, andIBM1across flowering plants. We identifyArabidopsisaccessions resembling weakibm1mutants and Brassicaceae species with reducedIBM1expression or deletions. Evolution towards reduced IBM1 activity in some flowering plants could explain the frequent natural occurrence of diminished or lost CMT3 activity and loss of gene body DNA methylation, ascmt3mutants inA.thalianamitigate the deleterious effects of IBM1. 

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5. Natural variation in DNA methylation homeostasis and the emergence of epialleles

   https://doi.org/10.1073/pnas.1918172117  

   Zhang, Yinwen; Wendte, Jered M.; Ji, Lexiang; Schmitz, Robert J. (February 2020, Proceedings of the National Academy of Sciences)

   In plants and mammals, DNA methylation plays a critical role in transcriptional silencing by delineating heterochromatin from transcriptionally active euchromatin. A homeostatic balance between heterochromatin and euchromatin is essential to genomic stability. This is evident in many diseases and mutants for heterochromatin maintenance, which are characterized by global losses of DNA methylation coupled with localized ectopic gains of DNA methylation that alter transcription. Furthermore, we have shown that genome-wide methylation patterns inArabidopsis thalianaare highly stable over generations, with the exception of rare epialleles. However, the extent to which natural variation in the robustness of targeting DNA methylation to heterochromatin exists, and the phenotypic consequences of such variation, remain to be fully explored. Here we describe the finding that heterochromatin and genic DNA methylation are highly variable among 725A. thalianaaccessions. We found that genic DNA methylation is inversely correlated with that in heterochromatin, suggesting that certain methylation pathway(s) may be redirected to genes upon the loss of heterochromatin. This redistribution likely involves a feedback loop involving the DNA methyltransferase, CHROMOMETHYLASE 3 (CMT3), H3K9me2, and histone turnover, as highly expressed, long genes with a high density of CMT3-preferred CWG sites are more likely to be methylated. Importantly, although the presence of CG methylation in genes alone may not affect transcription, genes containing CG methylation are more likely to become methylated at non-CG sites and silenced. These findings are consistent with the hypothesis that natural variation in DNA methylation homeostasis may underlie the evolution of epialleles that alter phenotypes. 

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