Maternal Loss-of-function of Nlrp2 Results in Failure of Epigenetic Reprogramming in Mouse Oocytes

Overview

Journal Res Sq

Date 2024 Jun 17

PMID 38883732

Authors

Zahra Anvar

Michael D Jochum

Imen Chakchouk

Momal Sharif

Hannah Demond

Alvin K To

Daniel C Kraushaar

Ying-Wooi Wan

Simon Andrews

Gavin Kelsey

Ignatia B Veyver

Affiliations

Soon will be listed here.

Abstract

Background: NLRP2 belongs to the subcortical maternal complex (SCMC) of mammalian oocytes and preimplantation embryos. This multiprotein complex, encoded by maternal-effect genes, plays a pivotal role in the zygote-to-embryo transition, early embryogenesis, and epigenetic (re)programming. The maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans. However, the underlying molecular mechanisms for the diverse functions of the SCMC, particularly how this cytoplasmic structure influences DNA methylation, which is a nuclear process, are not fully understood.

Results: We undertook joint transcriptome and DNA methylome profiling of pre-ovulatory germinal-vesicle oocytes from -null, heterozygous (Het), and wild-type (WT) female mice. We identified numerous differentially expressed genes (DEGs) in Het and -null when compared to WT oocytes. The genes for several crucial factors involved in oocyte transcriptome modulation and epigenetic reprogramming, such as DNMT1, UHRF1, KDM1B and ZFP57 were overexpressed in Het and -null oocytes. Absence or reduction of , did not alter the distinctive global DNA methylation landscape of oocytes, including the bimodal pattern of the oocyte methylome. Additionally, although the methylation profile of germline differentially methylated regions (gDMRs) of imprinted genes was preserved in oocytes of Het and -null mice, we found altered methylation in oocytes of both genotypes at a small percentage of the oocyte-characteristic hyper- and hypomethylated domains. Through a tiling approach, we identified specific DNA methylation differences between the genotypes, with approximately 1.3% of examined tiles exhibiting differential methylation in Het and -null compared to WT oocytes.

Conclusions: Surprisingly, considering the well-known correlation between transcription and DNA methylation in developing oocytes, we observed no correlation between gene expression differences and gene-body DNA methylation differences in -null versus WT oocytes or Het versus WT oocytes. We therefore conclude that post-transcriptional changes in the stability of transcripts rather than altered transcription is primarily responsible for transcriptome differences in -null and Het oocytes.

References

Kawai T, Richards J, Shimada M . Large-scale DNA demethylation occurs in proliferating ovarian granulosa cells during mouse follicular development. Commun Biol. 2021; 4(1):1334. PMC: 8617273. DOI: 10.1038/s42003-021-02849-w. View

Jentoft I, Bauerlein F, Welp L, Cooper B, Petrovic A, So C . Mammalian oocytes store proteins for the early embryo on cytoplasmic lattices. Cell. 2023; 186(24):5308-5327.e25. DOI: 10.1016/j.cell.2023.10.003. View

Ewels P, Magnusson M, Lundin S, Kaller M . MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics. 2016; 32(19):3047-8. PMC: 5039924. DOI: 10.1093/bioinformatics/btw354. View

Mahadevan S, Sathappan V, Utama B, Lorenzo I, Kaskar K, Van den Veyver I . Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming. Sci Rep. 2017; 7:44667. PMC: 5357799. DOI: 10.1038/srep44667. View

Krueger F, Andrews S . Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011; 27(11):1571-2. PMC: 3102221. DOI: 10.1093/bioinformatics/btr167. View

Ji S, Chen F, Stein P, Wang J, Zhou Z, Wang L . OBOX regulates mouse zygotic genome activation and early development. Nature. 2023; 620(7976):1047-1053. PMC: 10528489. DOI: 10.1038/s41586-023-06428-3. View

Anvar Z, Chakchouk I, Demond H, Sharif M, Kelsey G, Van den Veyver I . DNA Methylation Dynamics in the Female Germline and Maternal-Effect Mutations That Disrupt Genomic Imprinting. Genes (Basel). 2021; 12(8). PMC: 8394515. DOI: 10.3390/genes12081214. View

Tashiro F, Kanai-Azuma M, Miyazaki S, Kato M, Tanaka T, Toyoda S . Maternal-effect gene Ces5/Ooep/Moep19/Floped is essential for oocyte cytoplasmic lattice formation and embryonic development at the maternal-zygotic stage transition. Genes Cells. 2010; 15(8):813-28. DOI: 10.1111/j.1365-2443.2010.01420.x. View

Tong Z, Gold L, Pfeifer K, Dorward H, Lee E, Bondy C . Mater, a maternal effect gene required for early embryonic development in mice. Nat Genet. 2000; 26(3):267-8. DOI: 10.1038/81547. View

10.

Uemura S, Maenohara S, Inoue K, Ogonuki N, Matoba S, Ogura A . UHRF1 is essential for proper cytoplasmic architecture and function of mouse oocytes and derived embryos. Life Sci Alliance. 2023; 6(8). PMC: 10209520. DOI: 10.26508/lsa.202301904. View

11.

Fontana L, Bedeschi M, Maitz S, Cereda A, Fare C, Motta S . Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders. Epigenetics. 2018; 13(9):897-909. PMC: 6284780. DOI: 10.1080/15592294.2018.1514230. View

12.

Gahurova L, Tomizawa S, Smallwood S, Stewart-Morgan K, Saadeh H, Kim J . Transcription and chromatin determinants of de novo DNA methylation timing in oocytes. Epigenetics Chromatin. 2017; 10:25. PMC: 5429541. DOI: 10.1186/s13072-017-0133-5. View

13.

Bebbere D, Albertini D, Coticchio G, Borini A, Ledda S . The subcortical maternal complex: emerging roles and novel perspectives. Mol Hum Reprod. 2021; 27(7). DOI: 10.1093/molehr/gaab043. View

14.

Winata C, Korzh V . The translational regulation of maternal mRNAs in time and space. FEBS Lett. 2018; 592(17):3007-3023. PMC: 6175449. DOI: 10.1002/1873-3468.13183. View

15.

Yan R, Cheng X, Gu C, Xu Y, Long X, Zhai J . Dynamics of DNA hydroxymethylation and methylation during mouse embryonic and germline development. Nat Genet. 2022; 55(1):130-143. DOI: 10.1038/s41588-022-01258-x. View

16.

Eggermann T, Kadgien G, Begemann M, Elbracht M . Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family. Eur J Hum Genet. 2020; 29(4):575-580. PMC: 8115525. DOI: 10.1038/s41431-020-00762-0. View

17.

Wright P, Bolling L, Calvert M, Sarmento O, Berkeley E, Shea M . ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets. Dev Biol. 2003; 256(1):73-88. DOI: 10.1016/s0012-1606(02)00126-4. View

18.

Zheng W, Hu H, Dai J, Zhang S, Gu Y, Dai C . Expanding the genetic and phenotypic spectrum of the subcortical maternal complex genes in recurrent preimplantation embryonic arrest. Clin Genet. 2020; 99(2):286-291. DOI: 10.1111/cge.13858. View

19.

Lee M, Bonneau A, Giraldez A . Zygotic genome activation during the maternal-to-zygotic transition. Annu Rev Cell Dev Biol. 2014; 30:581-613. PMC: 4303375. DOI: 10.1146/annurev-cellbio-100913-013027. View

20.

Demond H, Anvar Z, Jahromi B, Sparago A, Verma A, Davari M . A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation. Genome Med. 2019; 11(1):84. PMC: 6918611. DOI: 10.1186/s13073-019-0694-y. View