Heterochromatin is a quantitative trait associated with spontaneous epiallele formation

• Published in: Nature communications Vol. 12; no. 1; p. 6958
• Main Authors: Zhang, Yinwen, Jang, Hosung, Xiao, Rui, Kakoulidou, Ioanna, Piecyk, Robert S., Johannes, Frank, Schmitz, Robert J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/15; 45/23; 631/208/176/1988; 631/337/100/101; 631/449/1659; Alleles; Arabidopsis - genetics; Arabidopsis - metabolism; Arabidopsis Proteins - genetics; Arabidopsis Proteins - metabolism; Chromatin; Chromosome Mapping; Deoxyribonucleic acid; DNA; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epigenesis, Genetic; Epigenetics; Euchromatin; Euchromatin - chemistry; Euchromatin - metabolism; Feedback; Feedback loops; Feedback, Physiological; Gene Expression Regulation, Plant; Gene Frequency; Gene mapping; Genes; Genome, Plant; Genomes; Haplotypes; Heterochromatin; Heterochromatin - chemistry; Heterochromatin - metabolism; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Inbreeding; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; multidisciplinary; Nucleotide sequence; Origins; Perturbation; Plants, Genetically Modified; Positive feedback; Protein Processing, Post-Translational; Quantitative Trait Loci; Science; Science (multidisciplinary); Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27320-6

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. The molecular origins of epialleles remain unknown. Here, the authors show that a positive feedback loop between H3K9me2 and CMT2/3 is a major contributing factor to the origins of spontaneous epialleles and that heterochromatin is a quantitative trait associated with spontaneous epiallele formation.