Abstract
Male and female brains differ significantly in both health and disease, and yet the female brain has been understudied. Sex-hormone fluctuations make the female brain particularly dynamic and are likely to confer female-specific risks for neuropsychiatric disorders. The molecular mechanisms underlying the dynamic nature of the female brain structure and function are unknown. Here we show that neuronal chromatin organization in the female ventral hippocampus of mouse fluctuates with the oestrous cycle. We find chromatin organizational changes associated with the transcriptional activity of genes important for neuronal function and behaviour. We link these chromatin dynamics to variation in anxiety-related behaviour and brain structure. Our findings implicate an immediate-early gene product, Egr1, as part of the mechanism mediating oestrous cycle-dependent chromatin and transcriptional changes. This study reveals extreme, sex-specific dynamism of the neuronal epigenome, and establishes a foundation for the development of sex-specific treatments for disorders such as anxiety and depression.
Highlights
Male and female brains differ significantly in both health and disease, and yet the female brain has been understudied
In terms of gene expression, the Hedgehog signalling pathway is specific to the proestrus–dioestrus comparison (Supplementary Data 8), and considering a similar enrichment found in the corresponding ATAC-seq data (Fig. 2a), our findings suggest that the oestrous cycle-dependent regulation of genes belonging to the Hedgehog pathway involves the control of local chromatin accessibility
This study reveals remarkable chromatin dynamics in the female brain in response to naturally cycling levels of sex hormones during the oestrous cycle
Summary
Male and female brains differ significantly in both health and disease, and yet the female brain has been understudied. We find chromatin organizational changes associated with the transcriptional activity of genes important for neuronal function and behaviour. The premenstrual dysphoric disorder, affecting 5–8% of women and requiring antidepressant treatment[15], strongly reflects an impact that natural hormonal shifts can have on female mood and well-being It is, of great importance to understand the molecular mechanisms that underlie the sex hormone-induced, dynamic nature of the female brain. We characterise the effect of the oestrous cycle and sex on neuronal chromatin accessibility and gene expression in the ventral hippocampus in relation to behavioural and structural phenotypes. Our study reveals an extreme dynamism of the female neuronal epigenome, associated with changes in gene expression, synaptic plasticity and anxiety-related behaviour, providing a paradigm and mechanism for studying sex differences in brain disorders
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