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Heterochromatin is a quantitative trait associated with spontaneous epiallele formation.

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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8630088 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Heterochromatin is a quantitative trait locus associated with spontaneous epiallele formation

Project description:Epialleles are meiotically inherited variations in expression states that are not linked to changes in DNA sequence. Although they are well documented to persist in plant genomes, their molecular origins are unknown. Here, we show using a variety of mutant and experimental populations that epialleles in Arabidopsis thaliana result from 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, with a preference for genes with pre-existing DNA methylation. Using epigenetic recombinant inbred lines (epiRIL), we show that epiallelic variation is enriched in euchromatin, yet, associated with QTL primarily located in heterochromatin. Mapping three-dimensional chromatin contacts reveals that genes that are hotspots for epiallelic variation have increased contact frequencies with regions possessing H3K9me2. Altogether, these data show that feedback regulation of pathways that evolved to maintain heterochromatin silencing leads to the origins of spontaneous epialleles.

2021-11-01 | GSE171157 | GEO

Heterochromatin is a quantitative trait locus associated with spontaneous epiallele formation

Project description:Heterochromatin is a quantitative trait locus associated with spontaneous epiallele formation

| PRJNA718567 | ENA

A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function.

Project description:Intracisternal A-particles (IAPs) are endogenous retroviruses (ERVs) responsible for most insertional mutations in the mouse. Full-length IAPs harbour genes flanked by long terminal repeats (LTRs). Here, we identify a solo LTR IAP variant (Iap5-1solo) recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (Iap5-1full), Iap5-1solo lacks DNA methylation and H3K9 trimethylation. The distinct DNA methylation levels between the two alleles are established during preimplantation development, likely due to loss of KRAB zinc finger protein binding at the Iap5-1solo variant. Iap5-1solo methylation increases and becomes more variable in a hybrid genetic background yet is unresponsive to maternal dietary methyl supplementation. Differential epigenetic modification of the two variants is associated with metabolic differences and tissue-specific changes in adjacent gene expression. Our characterisation of Iap5-1 as a genetically induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution.

| S-EPMC8084528 | biostudies-literature

Molecular dissection of formation of senescence-associated heterochromatin foci.

Project description:Senescence is characterized by an irreversible cell proliferation arrest. Specialized domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), are thought to contribute to the irreversible cell cycle exit in many senescent cells by repressing the expression of proliferation-promoting genes such as cyclin A. SAHF contain known heterochromatin-forming proteins, such as heterochromatin protein 1 (HP1) and the histone H2A variant macroH2A, and other specialized chromatin proteins, such as HMGA proteins. Previously, we showed that a complex of histone chaperones, histone repressor A (HIRA) and antisilencing function 1a (ASF1a), plays a key role in the formation of SAHF. Here we have further dissected the series of events that contribute to SAHF formation. We show that each chromosome condenses into a single SAHF focus. Chromosome condensation depends on the ability of ASF1a to physically interact with its deposition substrate, histone H3, in addition to its cochaperone, HIRA. In cells entering senescence, HP1gamma, but not the related proteins HP1alpha and HP1beta, becomes phosphorylated on serine 93. This phosphorylation is required for efficient incorporation of HP1gamma into SAHF. Remarkably, however, a dramatic reduction in the amount of chromatin-bound HP1 proteins does not detectably affect chromosome condensation into SAHF. Moreover, abundant HP1 proteins are not required for the accumulation in SAHF of histone H3 methylated on lysine 9, the recruitment of macroH2A proteins, nor other hallmarks of senescence, such as the expression of senescence-associated beta-galactosidase activity and senescence-associated cell cycle exit. Based on our results, we propose a stepwise model for the formation of SAHF.

| S-EPMC1820509 | biostudies-literature

Study of Quantitative Trait Loci (QTLs) Associated with Allelopathic Trait in Rice.

Project description:In rice there are few genetic studies reported for allelopathy traits, which signify the ability of plants to inhibit or stimulate growth of other plants in the environment, by exuding chemicals. QTL analysis for allelopathic traits were conducted with 98 F8 RILs developed from the cross between the high allelopathic parents of 'Sathi' and non-allelopathic parents of 'Nong-an'. The performance of allelopathic traits were evaluated with inhibition rate on root length, shoot length, total length, root weight, shoot weight, and total weight of lettuce as a receiver plant. With 785 polymorphic DNA markers, we constructed a linkage map showing a total of 2489.75 cM genetic length and 3.17 cM of average genetic distance between each adjacent marker. QTL analysis detected on QTL regions on chromosome 8 responsible for the inhibition of shoot length and inhibition of total length. The qISL-8 explained 20.38% of the phenotypic variation for the inhibition on the shoot length. The qITL-8 explained 14.93% of the phenotypic variation for the inhibition on total length. The physical distance of the detected QTL region was 194 Kbp where 31 genes are located.

| S-EPMC7290725 | biostudies-literature

RNA-seq analysis for detecting quantitative trait-associated genes.

Project description:Many recent RNA-seq studies were focused mainly on detecting the differentially expressed genes (DEGs) between two or more conditions. In contrast, only a few attempts have been made to detect genes associated with quantitative traits, such as obesity index and milk yield, on RNA-seq experiment with large number of biological replicates. This study illustrates the linear model application on trait associated genes (TAGs) detection in two real RNA-seq datasets: 89 replicated human obesity related data and 21 replicated Holsteins' milk production related RNA-seq data. Based on these two datasets, the performance between suggesting methods, such as ordinary regression and robust regression, and existing methods: DESeq2 and Voom, were compared. The results indicate that suggesting methods have much lower false discoveries compared to the precedent two group comparisons based approaches in our simulation study and qRT-PCR experiment. In particular, the robust regression outperforms existing DEG finding method as well as ordinary regression in terms of precision. Given the current trend in RNA-seq pricing, we expect our methods to be successfully applied in various RNA-seq studies with numerous biological replicates that handle continuous response traits.

| S-EPMC4829873 | biostudies-literature

A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci.

Project description:We conducted a comprehensive study of copy number variants (CNVs) well-tagged by SNPs (r(2)? 0.8) by analyzing their effect on gene expression and their association with disease susceptibility and other complex human traits. We tested whether these CNVs were more likely to be functional than frequency-matched SNPs as trait-associated loci or as expression quantitative trait loci (eQTLs) influencing phenotype by altering gene regulation. Our study found that CNV-tagging SNPs are significantly enriched for cis eQTLs; furthermore, we observed that trait associations from the NHGRI catalog show an overrepresentation of SNPs tagging CNVs relative to frequency-matched SNPs. We found that these SNPs tagging CNVs are more likely to affect multiple expression traits than frequency-matched variants. Given these findings on the functional relevance of CNVs, we created an online resource of expression-associated CNVs (eCNVs) using the most comprehensive population-based map of CNVs to inform future studies of complex traits. Although previous studies of common CNVs that can be typed on existing platforms and/or interrogated by SNPs in genome-wide association studies concluded that such CNVs appear unlikely to have a major role in the genetic basis of several complex diseases examined, our findings indicate that it would be premature to dismiss the possibility that even common CNVs may contribute to complex phenotypes and at least some common diseases.

| S-EPMC3033384 | biostudies-literature

The vaccinia virus K7 protein promotes histone methylation associated with heterochromatin formation.

Project description:It has been well established that many vaccinia virus proteins suppress host antiviral pathways by targeting the transcription of antiviral proteins, thus evading the host innate immune system. However, whether viral proteins have an effect on the host's overall cellular transcription is less understood. In this study we investigated the regulation of heterochromatin during vaccinia virus infection. Heterochromatin is a highly condensed form of chromatin that is less transcriptionally active and characterized by methylation of histone proteins. We examined the change in methylation of two histone proteins, H3 and H4, which are major markers of heterochromatin, during the course of viral infection. Using immunofluorescence microscopy and flow cytometry we were able to track the overall change in the methylated levels of H3K9 and H4K20. Our results suggest that there is significant increase in methylation of H3K9 and H4K20 during Orthopoxviruses infection compared to mock-infected cells. However, this effect was not seen when we infected cells with Leporipoxviruses. We further screened several vaccinia virus single and multi-gene deletion mutant and identified the vaccinia virus gene K7R as a contributor to the increase in cellular histone methylation during infection.

| S-EPMC5336242 | biostudies-literature

Polyphosphate drives bacterial heterochromatin formation.

Project description:Heterochromatin is most often associated with eukaryotic organisms. Yet, bacteria also contain areas with densely protein-occupied chromatin that appear to silence gene expression. One nucleoid-associated silencing factor is the conserved protein Hfq. Although seemingly nonspecific in its DNA binding properties, Hfq is strongly enriched at AT-rich DNA regions, characteristic of prophages and mobile genetic elements. Here, we demonstrate that polyphosphate (polyP), an ancient and highly conserved polyanion, is essential for the site-specific DNA binding properties of Hfq in bacteria. Absence of polyP markedly alters the DNA binding profile of Hfq, causes unsolicited prophage and transposon mobilization, and increases mutagenesis rates and DNA damage–induced cell death. In vitro reconstitution of the system revealed that Hfq and polyP interact with AT-rich DNA sequences and form phase-separated condensates, a process that is mediated by the intrinsically disordered C-terminal extensions of Hfq. We propose that polyP serves as a newly identified driver of heterochromatin formation in bacteria.

| S-EPMC10954037 | biostudies-literature

Loss of WSTF results in spontaneous fluctuations of heterochromatin formation and resolution, combined with substantial changes to gene expression.

Project description:BackgroundWilliams syndrome transcription factor (WSTF) is a multifaceted protein that is involved in several nuclear processes, including replication, transcription, and the DNA damage response. WSTF participates in a chromatin-remodeling complex with the ISWI ATPase, SNF2H, and is thought to contribute to the maintenance of heterochromatin, including at the human inactive X chromosome (Xi). WSTF is encoded by BAZ1B, and is one of twenty-eight genes that are hemizygously deleted in the genetic disorder Williams-Beuren syndrome (WBS).ResultsTo explore the function of WSTF, we performed zinc finger nuclease-assisted targeting of the BAZ1B gene and isolated several independent knockout clones in human cells. Our results show that, while heterochromatin at the Xi is unaltered, new inappropriate areas of heterochromatin spontaneously form and resolve throughout the nucleus, appearing as large DAPI-dense staining blocks, defined by histone H3 lysine-9 trimethylation and association of the proteins heterochromatin protein 1 and structural maintenance of chromosomes flexible hinge domain containing 1. In three independent mutants, the expression of a large number of genes were impacted, both up and down, by WSTF loss.ConclusionsGiven the inappropriate appearance of regions of heterochromatin in BAZ1B knockout cells, it is evident that WSTF performs a critical role in maintaining chromatin and transcriptional states, a property that is likely compromised by WSTF haploinsufficiency in WBS patients.

| S-EPMC3870985 | biostudies-literature

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