Feil Family Brain and Mind Research Institute Weill Cornell Medicine New York NY USA.
Endocrinol Diabetes Metab. 2020 Oct 9;4(1):e00191. doi: 10.1002/edm2.191. eCollection 2021 Jan.
Sex differences in brain cortical function affect cognition, behaviour and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Oestrogen and oestrogen receptors (ERs), specifically ERβ, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ERβ on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ERβ affects transcription.
In this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild-type and ERβ knockout mice (n = 4/sex/genotype). We used unbiased clustering to analyse whole-transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression.
We found only 27 significantly differentially expressed genes (DEGs) in wild-type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ERβKO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function 'cation channel activity'. Moreover, within each sex we found only a few DEGs in ERβKO vs WT mice (8 and 5 in males and females, respectively).
Overall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region-specific functional effects of ERβ may be largely post-transcriptional.
大脑皮质功能的性别差异会影响认知、行为和对神经疾病的易感性，但皮质功能性别二态性的分子基础在很大程度上仍不清楚。雌激素和雌激素受体（ERs），特别是 ERβ，是皮质中最丰富的 ER，可能在决定基因表达的性别差异中发挥作用，而这可能是功能性别差异的基础。然而，需要进一步的研究来解决性别和 ERβ对基因表达的影响在大脑区域的特异性。本研究的目的是研究小鼠后皮质中基因表达的性别差异，因为转录中的性别差异从未被研究过，并且确定 ERβ 的基因缺失如何影响转录。
在这项研究中，我们对成年野生型和 ERβ 敲除小鼠（n=4/性别/基因型）的后皮质 RNA 进行了无偏转录组学分析。我们使用无偏聚类分析来分析两组之间的全转录组变化。我们还使用 DESeq2 对数据进行差异表达分析，以确定基因表达的特定变化。
我们只在野生型（WT）雄性与雌性之间发现了 27 个显著差异表达基因（DEGs），其中 17 个是常染色体基因。有趣的是，在 ERβKO 雄性与雌性之间，所有的常染色体 DEGs 都消失了。对 WT 皮质中只有性别差异的 DEGs 进行的基因本体分析显示，注释为“阳离子通道活性”功能的基因显著富集。此外，在每个性别中，我们只在 ERβKO 与 WT 小鼠之间发现了少数 DEGs（雄性和雌性分别为 8 个和 5 个）。
总的来说，我们的研究结果表明，在成年小鼠后皮质中，基因表达的性别差异出人意料地少，而且这些差异主要与阳离子通道活性有关。此外，它们表明 ERβ 的大脑区域特异性功能影响可能主要是转录后。
