A Tissue Comparison of DNA Methylation of the Glucocorticoid Receptor Gene (Nr3c1) in European Starlings

Siller, Stefanie J; Rubenstein, Dustin R.

doi:10.1093/icb/icz034

Cited by 12 publications

(11 citation statements)

References 44 publications

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“…While there were differences in DNA methylation patterns in the blood, associated with urbanization, there was little evidence that this reflected a coordinated organismal response to environmental cues: sites of differential methylation between the two habitats were (i) not over‐represented in regulatory regions, (ii) less likely to occur in association with expressed genes, and (iii) not over‐represented in specific biological pathways; however, as in liver, DNA methylation in blood was negatively related to gene expression when DMSs were located in TSS regions. Although other studies have found DNA methylation patterns in blood to reflect environmental and social factors (Jimeno et al., 2019; Lea et al., 2016), tissue‐specific patterns of DNA methylation have been shown in mammals (Christensen et al., 2009) and birds (Siller & Rubenstein, 2019), and it is therefore not expected that all tissues will respond in the same way to environmental cues.…”

Section: Discussionmentioning

confidence: 98%

Urbanization is associated with modifications in DNA methylation in a small passerine bird

Watson

Powell

Salmón

et al. 2020

Evolutionary Applications

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Urbanization represents a fierce driver of phenotypic change, yet the molecular mechanisms underlying observed phenotypic patterns are poorly understood. Epigenetic changes are expected to facilitate more rapid adaption to changing or novel environments, such as our towns and cities, compared with slow changes in gene sequence. A comparison of liver and blood tissue from great tits Parus major originating from an urban and a forest site demonstrated that urbanization is associated with variation in genome‐wide patterns of DNA methylation. Combining reduced representation bisulphite sequencing with transcriptome data, we revealed habitat differences in DNA methylation patterns that suggest a regulated and coordinated response to the urban environment. In the liver, genomic sites that were differentially methylated between urban‐ and forest‐dwelling birds were over‐represented in regulatory regions of the genome and more likely to occur in expressed genes. DNA methylation levels were also inversely correlated with gene expression at transcription start sites. Furthermore, differentially methylated CpG sites, in liver, were over‐represented in pathways involved in (i) steroid biosynthesis, (ii) superoxide metabolism, (iii) secondary alcohol metabolism, (iv) chylomicron remodelling, (v) cholesterol transport, (vi) reactive oxygen species (ROS) metabolic process and (vii) epithelial cell proliferation. This corresponds with earlier studies identifying diet and exposure to ROS as two of the main drivers of divergence between organisms in urban and nonurban environments. Conversely, in blood, sites that were differentially methylated between urban‐ and forest‐dwelling birds were under‐represented in regulatory regions, more likely to occur in nonexpressed genes and not over‐represented in specific biological pathways. It remains to be determined whether diverging patterns of DNA methylation represent adaptive evolutionary responses and whether the conclusions can be more widely attributed to urbanization.

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Section: Discussionmentioning

confidence: 98%

Urbanization is associated with modifications in DNA methylation in a small passerine bird

Watson

Powell

Salmón

et al. 2020

Evolutionary Applications

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“…The fact that we found a significant association between methylation levels in this region and gene expression suggests that this region or nearby ones play a role in gene expression regulation, but this remains to be confirmed. Secondly, DNA methylation may diverge with cell type and among tissues 43,58 . The use of tissues that allow non-lethal sampling enables the collection of longitudinal data and becomes especially relevant in long-term studies, but whether different tissues show comparable epigenetic changes in response to environmental challenges or experimental manipulations remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Previous research suggests that epigenetic biomarkers in peripheral tissues (e.g. blood) may be used to test for long-term environmental effects on DNA methylation patterns 38–40 , also for the Nr3c1 gene 4,18,25,41,42 , which is further supported by the fact that methylation patterns in blood have often been shown to correlate with methylation patterns in other tissues such as the brain 15,26,27 , but see 43 .…”

Section: Methodsmentioning

confidence: 95%

Developmental conditions modulate DNA methylation at the glucocorticoid receptor gene with cascading effects on expression and corticosterone levels in zebra finches

Jimeno

Hau

Gómez‐Díaz

et al. 2019

Sci Rep

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Developmental conditions can impact the adult phenotype via epigenetic changes that modulate gene expression. In mammals, methylation of the glucocorticoid receptor gene Nr3c1 has been implicated as mediator of long-term effects of developmental conditions, but this evidence is limited to humans and rodents, and few studies have simultaneously tested for associations between DNA methylation, gene expression and phenotype. Adverse environmental conditions during early life (large natal brood size) or adulthood (high foraging costs) exert multiple long-term phenotypic effects in zebra finches, and we here test for effects of these manipulations on DNA methylation and expression of the Nr3c1 gene in blood. Having been reared in a large brood induced higher DNA methylation of the Nr3c1 regulatory region in adulthood, and this effect persisted over years. Nr3c1 expression was negatively correlated with methylation at 2 out of 8 CpG sites, and was lower in hard foraging conditions, despite foraging conditions having no effect on Nr3c1 methylation at our target region. Nr3c1 expression also correlated with glucocorticoid traits: higher expression level was associated with lower plasma baseline corticosterone concentrations and enhanced corticosterone reactivity. Our results suggest that methylation of the Nr3c1 regulatory region can contribute to the mechanisms underlying the emergence of long-term effects of developmental conditions in birds, but in our system current adversity dominated over early life experiences with respect to receptor expression.

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“…4E and SI Appendix, Fig. S5) following established protocols (39,40). These clusters varied according to allele (Fig.…”

Section: Resultsmentioning

confidence: 98%

A supergene-linked estrogen receptor drives alternative phenotypes in a polymorphic songbird

Merritt

Grogan

Zinzow-Kramer

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Behavioral evolution relies on genetic changes, yet few behaviors can be traced to specific genetic sequences in vertebrates. Here we provide experimental evidence showing that differentiation of a single gene has contributed to the evolution of divergent behavioral phenotypes in the white-throated sparrow, a common backyard songbird. In this species, a series of chromosomal inversions has formed a supergene that segregates with an aggressive phenotype. The supergene has captured ESR1, the gene that encodes estrogen receptor α (ERα); as a result, this gene is accumulating changes that now distinguish the supergene allele from the standard allele. Our results show that in birds of the more aggressive phenotype, ERα knockdown caused a phenotypic change to that of the less aggressive phenotype. We next showed that in a free-living population, aggression is predicted by allelic imbalance favoring the supergene allele. Finally, we identified cis-regulatory features, both genetic and epigenetic, that explain the allelic imbalance. This work provides a rare illustration of how genotypic divergence has led to behavioral phenotypic divergence in a vertebrate.

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A Tissue Comparison of DNA Methylation of the Glucocorticoid Receptor Gene (Nr3c1) in European Starlings

Cited by 12 publications

References 44 publications

Urbanization is associated with modifications in DNA methylation in a small passerine bird

Urbanization is associated with modifications in DNA methylation in a small passerine bird

Developmental conditions modulate DNA methylation at the glucocorticoid receptor gene with cascading effects on expression and corticosterone levels in zebra finches

A supergene-linked estrogen receptor drives alternative phenotypes in a polymorphic songbird

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