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Loss of the Maternal Effect Gene Nlrp2 Alters the Transcriptome of Ovulated Mouse Oocytes and Impacts Expression of Histone Demethylase KDM1B

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Abstract

The subcortical maternal complex (SCMC) is a multiprotein complex in oocytes and preimplantation embryos that is encoded by maternal effect genes. The SCMC is essential for zygote-to-embryo transition, early embryogenesis, and critical zygotic cellular processes, including spindle positioning and symmetric division. Maternal deletion of Nlrp2, which encodes an SCMC protein, results in increased early embryonic loss and abnormal DNA methylation in embryos. We performed RNA sequencing on pools of meiosis II (MII) oocytes from wild-type and Nlrp2-null female mice that were isolated from cumulus-oocyte complexes (COCs) after ovarian stimulation. Using a mouse reference genome-based analysis, we found 231 differentially expressed genes (DEGs) in Nlrp2-null compared to WT oocytes (123 up- and 108 downregulated; adjusted p < 0.05). The upregulated genes include Kdm1b, a H3K4 histone demethylase required during oocyte development for the establishment of DNA methylation marks at CpG islands, including those at imprinted genes. The identified DEGs are enriched for processes involved in neurogenesis, gland morphogenesis, and protein metabolism and for post-translationally methylated proteins. When we compared our RNA sequencing data to an oocyte-specific reference transcriptome that contains many previously unannotated transcripts, we found 228 DEGs, including genes not identified with the first analysis. Interestingly, 68% and 56% of DEGs from the first and second analyses, respectively, overlap with oocyte-specific hyper- and hypomethylated domains. This study shows that there are substantial changes in the transcriptome of mouse MII oocytes from female mice with loss of function of Nlrp2, a maternal effect gene that encodes a member of the SCMC.

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Data Availability

Data is publicly available from the Gene Expression Omnibus (GEO) accession number: GSE213059.

Code Availability

Not applicable.

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Funding

This work was supported by grants R01HD092746 and P50HD103555 (for use of the administrative core), from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health. M.S. is supported by postdoctoral fellowship award from The Lalor Foundation, INC and by T32HD098068. This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH NCI (P30CA125123) and CPRIT (RP200504) grants. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA

    Zahra Anvar, Imen Chakchouk, Momal Sharif, Sangeetha Mahadevan, Eleni Theodora Nasiotis, Li Su & Ignatia B. Van den Veyver

  2. Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Zahra Anvar, Imen Chakchouk, Momal Sharif, Sangeetha Mahadevan, Eleni Theodora Nasiotis, Li Su, Ying-Wooi Wan & Ignatia B. Van den Veyver

  3. Department of Pediatrics – Neurology, Baylor College of Medicine, Houston, TX, USA

    Zhandong Liu

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Ying-Wooi Wan & Ignatia B. Van den Veyver

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  1. Zahra Anvar
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  2. Imen Chakchouk
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  5. Eleni Theodora Nasiotis
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  8. Ying-Wooi Wan
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  9. Ignatia B. Van den Veyver
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Contributions

SM, YWW, and IV conceived the experiments; ZA, SM, IC, and ETN performed experiments; YWW, ZL, IC, LS, and MS analyzed data. ZA and IV wrote the manuscript. All authors contributed to manuscript editing. IV acquired funding and was responsible for overall oversight and final editing.

Corresponding authors

Correspondence to Ying-Wooi Wan or Ignatia B. Van den Veyver.

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All experiments were approved by the Baylor College of Medicine Institutional Animal Care and Use Committee (protocol AN-2035). Animal facilities were accredited by the Association for Assessment and Accreditation for Laboratory Animal Care International (AAALAC).

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Anvar, Z., Chakchouk, I., Sharif, M. et al. Loss of the Maternal Effect Gene Nlrp2 Alters the Transcriptome of Ovulated Mouse Oocytes and Impacts Expression of Histone Demethylase KDM1B. Reprod. Sci. 30, 2780–2793 (2023). https://doi.org/10.1007/s43032-023-01218-8

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