Role of Gene Body Methylation in Acclimatization and Adaptation in a Basal Metazoan

Role of gene body methylation in acclimatization and adaptation in a basal metazoan Groves Dixona, Yi Liaoa, Line K. Bayb, and Mikhail V. Matza,1 aDepartment of Integrative Biology, University of Texas at Austin, Austin, TX 78712; and bAustralian Institute of Marine Science, Townsville, QLD 4810, Australia Edited by Stephen R. Palumbi, Stanford University, Pacific Grove, CA, and approved November 12, 2018 (received for review August 9, 2018) Gene body methylation (GBM) has been hypothesized to modulate be to examine differences between populations, as has been re- responses to environmental change, including transgenerational cently done in plants (16, 17); however, this interpretation re- plasticity, but the evidence thus far has been lacking. Here we quires disentangling the effect of environment from the effect of show that coral fragments reciprocally transplanted between two genetic divergence among populations (18). As for transgenerational distant reefs respond predominantly by increase or decrease in plasticity, for GBM to be involved in this process it must be both genome-wide GBM disparity: The range of methylation levels responsive to the environment and heritable. This somewhat con- between lowly and highly methylated genes becomes either tradictory combination of properties has not yet been demonstrated wider or narrower. Remarkably, at a broad functional level this for GBM in any study system. simple adjustment correlated very well with gene expression Here, we used a reciprocal transplantation framework (19) to change, reflecting a shifting balance between expressions of test for the roles of GBM in local adaptation and acclimatization environmentally responsive and housekeeping genes. In our in a reef-building coral Acropora millepora. Corals are basal experiment, corals in a lower-quality habitat up-regulated genes metazoans of the phylum Cnidaria with many ancestral genomic involved in environmental responses, while corals in a higher- features common to all multicellular animals, including humans quality habitat invested more in housekeeping genes. Trans- (20, 21). Most importantly for this study, corals possess the planted fragments showing closer GBM match to local corals typical metazoan gene body methylation (9) that is lacking in attained higher fitness characteristics, which supports GBM’s role highly evolutionarily derived models such as Drosophila and GENETICS in acclimatization. Fixed differences in GBM between populations Caenorhabditis (5). In addition, the possibility of clonal replica- did not align with plastic GBM changes and were mostly observed tion via fragmentation of coral colonies makes disentangling the in genes with elevated FST, which suggests that they arose pre- effects of genotype and environment very straightforward, solv- dominantly through genetic divergence. However, we cannot ing a major problem of ecological epigenetics (18). completely rule out transgenerational inheritance of acquired We have compared corals from two reefs, Orpheus Island in GBM states. the central sector of the Great Barrier Reef (GBR) and Keppel Island in the south of the GBR (Fig. 1A). These reefs are notably DNA methylation | coral | reciprocal transplant | gene expression | fitness different in temperature (Fig. 1B) as well as several other abi- otic parameters (22) and host slightly genetically divergent ene body methylation (GBM) is a taxonomically widespread Gepigenetic modification the function of which remains Significance enigmatic (1, 2). Only the detrimental effect of GBM is well understood: GBM causes hypermutability in protein-coding re- Whether epigenetics can facilitate persistence of acquired gions (3). Indeed, in humans, GBM is the primary driver of adaptive traits remains hotly debated. Here we use a primitive deleterious parent-age–related mutations (4). To merit pervasive multicellular animal, a reef-building coral, to address this ques- evolutionary conservation, the fundamental biological function tion for gene body methylation, which is a common epigenetic of GBM must be important enough to outweigh this risk (1). modification in organisms ranging from sunflowers to humans. One remarkable feature of GBM throughout Metazoa is its We show that gene body methylation is altered by the envi- bimodal distribution among functional categories of genes: GBM ronment in an unexpectedly simple way that reflects a shifting is high in ubiquitously expressed housekeeping genes and low in balance between expressions of housekeeping and environ- genes that are regulated, depending on the context (2, 5). It has mentally responsive genes, which helps acclimatization. Whether been proposed that GBM suppresses intragenic transcription these changes contribute to longer-term adaptation remains an initiation in highly expressed genes (6, 7), while other authors open question: While the majority of fixed epigenetic differences argued that GMB simply accumulates in actively transcribed between populations do not appear to be due to fixation of chromatin (8). Still, the correlation of GBM level with gene plastic changes, their transgenerational inheritance cannot be expression (9, 10) is weak and cannot explain the striking bi- completely ruled out. modality of GBM among functional groups of genes. The ecological genomic literature has long expected that GBM (as well Author contributions: L.K.B. and M.V.M. designed research; G.D., L.K.B., and M.V.M. per- formed research; G.D., Y.L., and M.V.M. analyzed data; and G.D., L.K.B., and M.V.M. as other epigenetic marks) can respond to the environment and wrote the paper. assist acclimatization by modulating gene expression, possibly The authors declare no conflict of interest. across generations (11–13). Still, thus far the only well-documented This article is a PNAS Direct Submission. case of GBM responding to the environment and resulting in phenotype change is determination of castes in social insects, Published under the PNAS license. depending on diet (14). Beyond this highly taxon-specific ex- Data deposition: TagSeq, MBD-seq, and amplicon-bisulfite sequencing datasets have been deposited in the NCBI Short Read Archive (project accession no. SRP049522) on February ample, GBM response to the environment has been reported in 28, 2018. Scripts and traits data have been deposited in a GitHub repository (https:// a recent paper comparing symbiotic and symbiont-free states of github.com/z0on/coral_GBM_RecipTrans) on November 1, 2018. a sea anemone (10) and in a paper on coral acclimatization to 1To whom correspondence should be addressed. Email: [email protected]. acidic conditions (15); notably, no clear correlation between This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. changes in GBM and changes in gene expression has been re- 1073/pnas.1813749115/-/DCSupplemental. covered. One way to address the role of GBM in adaptation would www.pnas.org/cgi/doi/10.1073/pnas.1813749115 PNAS Latest Articles | 1of5 Downloaded by guest on September 29, 2021 A these results by bisulfite sequencing 13 amplicons representing low- B to middle-level MBD scores and found that an MBD-score range from −3 to 1 corresponded to the range of methylation levels between 1% and 30% (SI Appendix,Fig.S1B). Genome-wide vali- dation of our MBD-seq data was also provided by the facts that the N=15 MBD score exhibited the expected bimodal distribution across genes (SI Appendix,Fig.S1A) and showed strong correlation with the established proxy of historical methylation level, the ratio of observed to expected numbers of CpG dinucleotides (Fig. 2D)(5). Relative quantification results based only on MBD-captured read N=15 data were nearly identical to those obtained when using both captured and flow-through fractions (SI Appendix,Fig.S2), and so for the remaining 32 samples we sequenced only the MBD- CD captured fraction. For GBM, we analyzed 27,084 genes (of 32,045 total anno- tated genes in the Acropora digitifera genome, which was used as a reference) with mean counts across samples equal to or greater than 20. Gene expression (GE) analysis used the dataset published previously (28), which included 19,706 genes. Multivariate analysis of GE and GBM (SI Appendix, Fig. S3) revealed that GBM is more consistent across fragments of the same original colony than GE, resulting in the estimate of broad-sense heri- tability of 0.79 compared with 0.64 for GE (SI Appendix, Fig. S3C). In addition, significant effects of origin and transplantation site were observed for GE and GBM, both more pronounced for GE (SI Appendix, Fig. S3C). Fig. 1. Overview of the experiment. (A) Design of reciprocal transplanta- Surprisingly, the change in GBM in response to transplantation. (B) A. millepora.(C) Temperature profiles at the transplantation sites, historical (thick lines) and during the year of experiment (thin lines). (D) tion from Orpheus to Keppel consisted mainly of genome-wide Principal component analysis of the four fitness proxies: weight gain and reduction of disparity between highly and lowly methylated genes: lipid, protein, and carbohydrate content. In the sample names, the first letter Highly methylated genes became less methylated and lowly is the origin location and the second letter is transplantation location. methylated genes became more methylated (Fig. 2A, Top). This change was mirrored by less pronounced but clearly reciprocal GBM adjustment in Keppel corals transplanted to Orpheus (Fig. A. millepora populations (23, 24). From each reef, 15 coral

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