Examination of CA1 Hippocampal DNA Methylation as a Mechanism for Closing of Estrogen’s Critical Window

Abstract

There is a critical window for estrogen replacement therapy, beyond which estradiol (E2) fails to enhance cognition and N-methyl-D-aspartate (NMDA) receptor function, and E2-responsive transcription decreases. Much less attention has been given to the mechanism for closing of the critical window, which is thought to involve the decline in estrogen signaling cascades, possibly involving epigenetic mechanisms, including DNA methylation. This study investigated changes in DNA methylation in region CA1 of the hippocampus of ovariectomized female rats over the course of brain aging and in response to E2-treatment, using whole genome bisulfite sequencing. Differential methylation of CpG and non-CpG (CHG and CHH) sites and associated genes were characterized in aged controls (AC), middle-age controls (MC), and young controls (YC) and differential methylation in response to E2-treatment (T) was examined in each age group (AT-AC, MT-MC, and YT-YC). Possible candidate genes for the closing of the critical window were defined as those that were hypomethylated by E2-treatment in younger animals, but were unresponsive in aged animals. Gene ontology categories for possible critical window genes were linked to response to hormones (Adcyap1, Agtr2, Apob, Ahr, Andpro, Calm2, Cyp4a2, Htr1b, Nr3c2, Pitx2, Pth, Pdk4, Slc2a2, Tnc, and Wnt5a), including G-protein receptor signaling (Gpr22 and Rgs4). Other possible critical window genes were linked to glutamate synapses (Nedd4, Grm1, Grm7, and Grin3a). These results suggest that decreased E2 signaling with advanced age, and/or prolonged E2 deprivation, results in methylation of E2-responsive genes, including those involved in rapid E2 signaling, which may limit subsequent transcription.

Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection

“…This is likely due to the involvement of other reproductive hormones including menopausal rises in gonadotropins whose receptors are also expressed centrally and are known to regulate cognition (reviewed in: [ 38 , 39 ] and recently published in [ 40 ]. As estradiol withdrawal progresses, genes that normally respond to estradiol undergo epigenetic regulation (primarily methylation), which may decrease transcription and mute downstream effects [ 41 ].…”

Senolytic treatment alleviates doxorubicin‐induced chemobrain

“…Although genes linked to the immune response, oxidative stress, and cellular senescence were significantly upregulated in the Dox group, the number of genes was below the level needed to be considered a significant cluster. The difference in the brain's transcriptional response to Dox treatment, relative to aging, may relate to the transcriptional resilience of young animals in the face of systemic inflammation (Barter et al., 2020 ) or to the duration of inflammation and age‐related epigenetic changes that contribute to altered gene expression (Barter & Foster, 2018 ; Ianov, Riva, et al., 2017 ; Rani et al., 2022 ; Sinha et al., 2021 ).…”

Influence of age and sex on microRNA response and recovery in the hippocampus following sepsis

“…Epigenetic changes over the course of aging or due to the history of infection can either prime the brain to respond to immune stimulation or result in immune tolerance [14,98,99]. In this way, epigenetics regulates transcriptional responsiveness and susceptibility or resilience to stressors of aging, including systemic inflammation [14,25,100,101]. Table 3 provides a summary of biological functions related to neuroinflammation, neuroprotection, neurodegeneration, and cognition for some of the 22 miRs, which were increased in older male mice, and may contribute to differences in transcription and susceptibility or resilience to cognitive impairment.…”