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Differential regulation of hippocampal transcriptome by circulating estrogen

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Abstract

Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders.

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Data availability

All data analyzed and related to the publication of this manuscript are available from the corresponding author upon reasonable request. The RNA-seq data will be deposited to NCBI upon acceptance of the manuscript.

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Acknowledgments

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Funding

This work was supported by grants from the National Natural Science Foundation of China (32250410298), the Science and Technology Planning Project of Shenzhen Municipality (KCXFZ20211020164543007, 20210617155253001), the Fund of Development and Reform Commission of Shenzhen Municipality (XMHT20220104028), the Guangdong Basic and Applied Basic Research Foundation (2021A1515012141) and the Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP013).

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Authors and Affiliations

  1. Shenzhen Graduate School, Peking University, Shenzhen, China

    Javed Iqbal & Geng-Di Huang

  2. Department of Addiction Medicine, Shenzhen Engineering Research Center for Precision Psychiatric Technology, Shenzhen Clinical Research Center for Mental Disorders, Shenzhen Kangning Hospital & Shenzhen Mental Health Center, No.77 Zhenbi Road, Pingshan District, Shenzhen, 518118, Guangdong, China

    Javed Iqbal, Geng-Di Huang, Mei Yang & Xiao-Jian Jia

  3. Department of Biological Sciences, International Islamic University, Islamabad, Pakistan

    Maryam Bibi & Jabbar Zaman Khan Khatttak

  4. National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China

    Yan-Xue Xue

  5. Clinical College of Mental Health, Shenzhen University Health Science Center, Shenzhen, China

    Mei Yang & Xiao-Jian Jia

  6. Affiliated Mental Health Center, Southern University of Science and Technology, Shenzhen, China

    Mei Yang & Xiao-Jian Jia

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  1. Javed Iqbal
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Contributions

Author JI and MBB designed and performed the experiment. JI, and JZKK analyzed the data. JI and MBB wrote the original draft of the manuscript. JI, HGD, XJJ, YM, XYX, and JZKK helped in proofreading. All authors read and accepted the final version of this manuscript.

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Correspondence to Mei Yang or Xiao-Jian Jia.

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Supplementary information

ESM 1

Supplementary Table 1. List of Primers used in Real-Time quantitative PCR. (DOCX 18 kb)

ESM 2

Supplementary Table 2. List of estrogen-regulated differentially expressed genes (DEGs) of proestrus (PE) and diestrus (DE) stages involved in cellular, molecular and biological pathways. (XLSX 91 kb)

ESM 3

Supplementary Table 3. List of all KEGG pathways enrichment regulated by the differentially expressed genes (DEGs) of proestrus (PE) and diestrus (DE) stages. (XLS 45 kb)

ESM 4

Supplementary Table 4. The top significant enrichment of KEGG pathways regulated by the differentially expressed genes (DEGs) of proestrus (PE) and diestrus (DE) stages. (XLS 26 kb)

ESM 5

Supplementary Fig. 1. Classification of estrogen-regulated differentially expressed genes (DEGs) into cellular, molecular and biological processes. (PDF 156 kb)

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Iqbal, J., Bibi, M., Huang, GD. et al. Differential regulation of hippocampal transcriptome by circulating estrogen. Funct Integr Genomics 23, 309 (2023). https://doi.org/10.1007/s10142-023-01234-6

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