Epigenetics of the frozen brain: roles for lysine methylation in hypometabolism

Abstract

Wood frog (Rana sylvatica) freeze tolerance necessitates metabolic rate depression, where costly processes such as gene transcription are commonly suppressed. Epigenetic mechanisms, such as histone lysine methylation, have recently been implicated in hypometabolic states of various animals, although they are underreported in nervous tissues. In the present study, we track the expression of eight lysine methyltransferases, as well as the activity on, and abundance of putative histone products across the freeze-thaw cycle and freeze-associated substresses (anoxia, dehydration) of wood frog brains. Our results suggest that hypomethylation of transcriptionally repressive H3K9 may be a key facet of metabolic recovery during the thawing of nervous tissue, which we speculate may have a positive effect on global gene transcription. Some nonhistone roles for lysine methylation are also proposed.

MicroRNA transcriptomics in liver of the freeze‐tolerant gray tree frog (Dryophytes versicolor) indicates suppression of energy‐expensive pathways

“…Nuclear processes involved in chromatin organization and remodeling, as well as chromatin modification, methylation, and histone association were targeted during freezing (Figures 4–5). While histone methylation has not been examined in tree frogs, it has been studied in the freeze‐tolerant wood frog, R. sylvatica , where it was found to display a tissue‐specific response for both histone methyltransferases and histone methyl marks across freeze‐thaw cycles 61,62 …”

Histone Arginine Methylation in the Freeze-tolerant Wood Frog, Rana sylvatica

“…Interestingly, these studies suggest that the histone methylation response is not consistent either across species or among tissues, which is likely due to the tissue-and species-specific functions required over a stress-recovery episode (Bloskie and Storey, 2022;Hawkins and Storey, 2018;Watts and Storey, 2019;Wijenayake and Storey, 2016). Nevertheless, the results for arginine methylation in the present thesis show that, similar to lysine methylation, this posttranslational modification probably also contributes to the regulation of gene expression in liver as supported by the differential regulation of PRMTs and downstream targets.…”

“…sylvatica, to control their metabolic responses under stress conditions (Bloskie & Storey, 2022;Morin & Storey, 2009;Storey, 2015;Zhang et al, 2020).…”

“…Based on previous information about the general involvement of histone methylation in transcription control, initial research on the subject with R. sylvatica was carried out to study the involvement of lysine methylation in the regulation of metabolic rate depression in different tissues (Bloskie and Storey, 2022;Hawkins and Storey, 2018). However, further research was needed to evaluate how arginine methylation on histones was regulated in the wood frog under stress conditions.…”

“…TDRD3) and 'eraser' proteins (other demethylases) within the 'writer/reader/eraser' paradigm. Furthermore, an even larger number of KDMs exist and only a subset of them have been examined in the context of freezing survival (Bloskie and Storey, 2022;Hawkins and Storey, 2018). Another interesting avenue to pursue would be the functional significance of H4R3m2a and PRMT1 knockdown over the freeze/thaw cycle.…”