Corticosterone dynamically regulates retrotransposable element expression in the rat hippocampus and C6 cells

Abstract

The hippocampus is a highly plastic brain region sensitive to environmental stress. It shows dynamic changes in epigenetic marks associated with stress related learning. Previous work has shown that acute stress induces substantial transient changes in histone H3 lysine 9 trimethylation (H3K9me3). Moreover, increased H3K9me3 is enriched in hippocampal gene deserts accumulating within endogenous retroviruses and transposable elements. We have found that in response to acute glucocorticoid treatment, a similar change in global H3K9me3 is observed. However, when localized we found that H3K9me3 is markedly decreased at B2 short interspersed nuclear elements but not within intracisternal-A particle endogenous retroviruses. Further, decreased H3K9me3 valence within B2 elements was associated with increased transcript abundance. These data demonstrate the capacity for acute glucocorticoids to mobilize transposable elements via epigenetic unmasking. Reconciled with previous findings following acute stress, this suggests the capacity for mobile elements to potentially function as novel regulators given their dynamic regulation by stress and glucocorticoids.

B2 SINE RNA as a novel regulator of glucocorticoid receptor transcriptional activity

“…C6 cells (ATCC) were cultured in DMEM supplemented with 10% fetal bovine serum (ThermoScientific). Cells were otherwise cultured and passaged according to standard protocols (ATCC) ( Bartlett et al, 2021a ) ( Benda et al, 1968 ). Cells were maintained in log-phase growth and switched to serum deprived DMEM media 24 h prior to experiments.…”

“…Fixed cells were lysed and subjected to immunoprecipitation as previously described ( Bartlett et al, 2021a ; Bartlett and Hunter, 2019 ). In short, lysates were sheared with the Covaris M220 using the Covaris truChIP kit (Covaris) to produce achieve a chromatin smear between 200 and 600bp.…”

“…It has long been noted that many steroid receptor binding sites derive from transposon insertions, particularly short interspersed nuclear elements (SINE), and the role of transposons in both genome and epigenome evolution is a significant one ( Hunter, 2020 ; Lapp and Hunter, 2016 ). Further, Our own work has shown that stress and glucocorticoids regulate the expression of at least some of these elements ( Hunter et al, 2012 ; Bartlett et al, 2021a ).…”

“…The consequences of this interaction are the sequestration of the receptor, activated GR binds preferentially to the GAS5 transcript and not to GREs within the genome attenuating GR-induced transcription of the locus ( Kino et al, 2010 ), thus acting as an antagonist for GRs transcriptional activity. Using C6 glioblastoma cells, which express high levels of GR and have been used previously in our lab to model transcriptional interactions between transposable elements and GR ( Beaumont, 1985 ) ( Bartlett et al, 2021a ), we sought to examine the interactions between B2 SINE RNA and the GR. We have found that B2 SINE RNA contains a similar pseudo-GRE motif of which activated GR interacts with directly and herein describe the consequences of B2 SINE RNA on GR-induced transcription, which display a higher degree of complexity than the simple antagonism observed with GAS5.…”

Bridging the Gap Between Environmental Adversity and Neuropsychiatric Disorders: The Role of Transposable Elements

“…B2 SINE expression in the amygdala and hippocampus appears to be regulated by stress, where levels of B2 RNA have been shown to predict coping strategies in a sex specific fashion ( Hunter et al, 2012 ; Lambert et al, 2020 ). Furthermore, glucocorticoids have been shown to promote B2 SINE mobilization de novo in the hippocampus and in cell lines ( Bartlett et al, 2021 ), further underscoring the explicit interactions that occur between stress and the deep genome. These results support the notion that environmental stressors mediate TE activity through the promotion of interactions with the glucocorticoid receptor.…”