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1. Associations between DNA methylation and gene regulation depend on chromatin accessibility during transgenerational plasticity

   https://doi.org/10.1186/s12915-023-01645-8  

   Bogan, Samuel N. ; Strader, Marie E. ; Hofmann, Gretchen E. ( June 2023 , BMC Biology)

   Epigenetic processes are proposed to be a mechanism regulating gene expression during phenotypic plasticity. However, environmentally induced changes in DNA methylation exhibit little-to-no association with differential gene expression in metazoans at a transcriptome-wide level. It remains unexplored whether associations between environmentally induced differential methylation and expression are contingent upon other epigenomic processes such as chromatin accessibility. We quantified methylation and gene expression in larvae of the purple sea urchinStrongylocentrotus purpuratusexposed to different ecologically relevant conditions during gametogenesis (maternal conditioning) and modeled changes in gene expression and splicing resulting from maternal conditioning as functions of differential methylation, incorporating covariates for genomic features and chromatin accessibility. We detected significant interactions between differential methylation, chromatin accessibility, and genic feature type associated with differential expression and splicing.

   Differential gene body methylation had significantly stronger effects on expression among genes with poorly accessible transcriptional start sites while baseline transcript abundance influenced the direction of this effect. Transcriptional responses to maternal conditioning were 4–13 × more likely when accounting for interactions between methylation and chromatin accessibility, demonstrating that the relationship between differential methylation and gene regulation is partially explained by chromatin state.

   DNA methylation likely possesses multiple associations with gene regulation during transgenerational plasticity inS. purpuratusand potentially other metazoans,but its effects are dependent on chromatin accessibility and underlying genic features.

    

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2. Epigenomic divergence correlates with sequence polymorphism in Arabidopsis paralogs

   https://doi.org/10.1111/nph.19227  

   Kenchanmane Raju, Sunil K. ; Lensink, Mariele ; Kliebenstein, Daniel J. ; Niederhuth, Chad ; Monroe, Grey ( August 2023 , New Phytologist)

   Processes affecting rates of sequence polymorphism are fundamental to the evolution of gene duplicates. The relationship between gene activity and sequence polymorphism can influence the likelihood that functionally redundant gene copies are co‐maintained in stable evolutionary equilibria vs other outcomes such as neofunctionalization.

   Here, we investigate genic variation in epigenome‐associated polymorphism rates inArabidopsis thalianaand consider whether these affect the evolution of gene duplicates. We compared the frequency of sequence polymorphism and patterns of genetic differentiation between genes classified by exon methylation patterns: unmethylated (unM), gene‐body methylated (gbM), and transposon‐like methylated (teM) states, which reflect divergence in gene expression.

   We found that the frequency of polymorphism was higher in teM (transcriptionally repressed, tissue‐specific) genes and lower in gbM (active, constitutively expressed) genes. Comparisons of gene duplicates were largely consistent with genome‐wide patterns – gene copies that exhibit teM accumulate more variation, evolve faster, and are in chromatin states associated with reduced DNA repair.

   This relationship between expression, the epigenome, and polymorphism may lead to the breakdown of equilibrium states that would otherwise maintain genetic redundancies. Epigenome‐mediated polymorphism rate variation may facilitate the evolution of novel gene functions in duplicate paralogs maintained over evolutionary time.

    

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3. Natural methylation epialleles correlate with gene expression in maize

   https://doi.org/10.1093/genetics/iyad146  

   Zeng, Yibing ; Dawe, R Kelly ; Gent, Jonathan I ( August 2023 , GENETICS)

   Bomblies, K (Ed.)

   DNA methylation in plants is depleted from cis-regulatory elements in and near genes but is present in some gene bodies, including exons. Methylation in exons solely in the CG context is called gene body methylation (gbM). Methylation in exons in both CG and non-CG contexts is called TE-like methylation (teM). Assigning functions to both forms of methylation in genes has proven to be challenging. Toward that end, we utilized recent genome assemblies, gene annotations, transcription data, and methylome data to quantify common patterns of gene methylation and their relations to gene expression in maize. We found that gbM genes exist in a continuum of CG methylation levels without a clear demarcation between unmethylated genes and gbM genes. Analysis of expression levels across diverse maize stocks and tissues revealed a weak but highly significant positive correlation between gbM and gene expression except in endosperm. gbM epialleles were associated with an approximately 3% increase in steady-state expression level relative to unmethylated epialleles. In contrast to gbM genes, which were conserved and were broadly expressed across tissues, we found that teM genes, which make up about 12% of genes, are mainly silent, are poorly conserved, and exhibit evidence of annotation errors. We used these data to flag teM genes in the 26 NAM founder genome assemblies. While some teM genes are likely functional, these data suggest that the majority are not, and their inclusion can confound the interpretation of whole-genome studies.

    

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4. Developmental programming of DNA methylation and gene expression patterns is associated with extreme cardiovascular tolerance to anoxia in the common snapping turtle

   https://doi.org/10.1186/s13072-021-00414-7  

   Ruhr, Ilan ; Bierstedt, Jacob ; Rhen, Turk ; Das, Debojyoti ; Singh, Sunil Kumar ; Miller, Soleille ; Crossley, II, Dane A. ; Galli, Gina L. J. ( September 2021 , Epigenetics & Chromatin)

   Environmental fluctuation during embryonic and fetal development can permanently alter an organism’s morphology, physiology, and behaviour. This phenomenon, known as developmental plasticity, is particularly relevant to reptiles that develop in subterranean nests with variable oxygen tensions. Previous work has shown hypoxia permanently alters the cardiovascular system of snapping turtles and may improve cardiac anoxia tolerance later in life. The mechanisms driving this process are unknown but may involve epigenetic regulation of gene expression via DNA methylation. To test this hypothesis, we assessed in situ cardiac performance during 2 h of acute anoxia in juvenile turtles previously exposed to normoxia (21% oxygen) or hypoxia (10% oxygen) during embryogenesis. Next, we analysed DNA methylation and gene expression patterns in turtles from the same cohorts using whole genome bisulfite sequencing, which represents the first high-resolution investigation of DNA methylation patterns in any reptilian species.

   Genome-wide correlations between CpG and CpG island methylation and gene expression patterns in the snapping turtle were consistent with patterns observed in mammals. As hypothesized, developmental hypoxia increased juvenile turtle cardiac anoxia tolerance and programmed DNA methylation and gene expression patterns. Programmed differences in expression of genes such asSCN5Amay account for differences in heart rate, while genes such asTNNT2andTPM3may underlie differences in calcium sensitivity and contractility of cardiomyocytes and cardiac inotropy. Finally, we identified putative transcription factor-binding sites in promoters and in differentially methylated CpG islands that suggest a model linking programming of DNA methylation during embryogenesis to differential gene expression and cardiovascular physiology later in life. Binding sites for hypoxia inducible factors (HIF1A, ARNT, and EPAS1) and key transcription factors activated by MAPK and BMP signaling (RREB1 and SMAD4) are implicated.

   Our data strongly suggests that DNA methylation plays a conserved role in the regulation of gene expression in reptiles. We also show that embryonic hypoxia programs DNA methylation and gene expression patterns and that these changes are associated with enhanced cardiac anoxia tolerance later in life. Programming of cardiac anoxia tolerance has major ecological implications for snapping turtles, because these animals regularly exploit anoxic environments throughout their lifespan.

    

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5. Changes in gene body methylation do not correlate with changes in gene expression in Anthozoa or Hexapoda

   https://doi.org/10.1186/s12864-022-08474-z  

   Dixon, Groves ; Matz, Mikhail ( December 2022 , BMC Genomics)

   Abstract Background As human activity alters the planet, there is a pressing need to understand how organisms adapt to environmental change. Of growing interest in this area is the role of epigenetic modifications, such as DNA methylation, in tailoring gene expression to fit novel conditions. Here, we reanalyzed nine invertebrate (Anthozoa and Hexapoda) datasets to validate a key prediction of this hypothesis: changes in DNA methylation in response to some condition correlate with changes in gene expression. Results In accord with previous observations, baseline levels of gene body methylation (GBM) positively correlated with transcription, and negatively correlated with transcriptional variation between conditions. Correlations between changes in GBM and transcription, however, were negligible. There was also no consistent negative correlation between methylation and transcription at the level of gene body methylation class (either highly- or lowly-methylated), anticipated under the previously described “seesaw hypothesis”. Conclusion Our results do not support the direct involvement of GBM in regulating dynamic transcriptional responses in invertebrates. If changes in DNA methylation regulate invertebrate transcription, the mechanism must involve additional factors or regulatory influences. 

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