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Series GSE166586 Query DataSets for GSE166586
Status Public on Jun 28, 2021
Title Paternal MTHFR deficiency leads to reproductive decline across generations in association with hypomethylation of young retrotransposons
Organism Mus musculus
Experiment type Methylation profiling by high throughput sequencing
Summary 5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in the folate metabolic pathway with a key role in generating methyl groups. As MTHFR deficiency impacts male fertility and sperm DNA methylation, there is the potential for epimutations to be passed to the next generation. Here, we assessed whether the impact of MTHFR deficiency on testis morphology and sperm DNA methylation is exacerbated across generations. While MTHFR deficiency in F1 fathers has only minor effects on sperm counts and testis weights and histology, F2 generation sons show further deterioration in reproductive parameters. Extensive loss of DNA methylation is observed in both F1 and F2 sperm, with >80% of sites shared between generations, suggestive of regions consistently susceptible to MTHFR deficiency. These regions are generally methylated during late prenatal germ cell development and are enriched in young retrotransposons. As retrotransposons are resistant to reprogramming of DNA methylation in prenatal germ cells, their hypomethylated state in the sperm of F1 males could contribute to the worsening reproductive phenotype observed in F2 MTHFR- deficient males, findings compatible with the intergenerational passage of epimutations.
Overall design In order to study the reproductive health of Mthfr mice across generations, Mthfr +/- mice were mated in order to obtain an F1 generation of both Mthfr +/+ and Mthfr -/- male mice. Upon sexual maturity, male mice of the F1 generation were mated with Mthfr +/- mice to obtain the F2 generation. An external cohort of mice (Mat_Def_colony) was also examined, where maternal- and paternal-deficient Mthfr mice were mated to obtain Mthfr -/- male mice.
Contributor(s) Karahan G, Chan D, Shirane K, McClatchie T, Janssen S, Baltz J, Lorincz M, Trasler J
Citation(s) 34128976
Submission date Feb 10, 2021
Last update date Jul 27, 2021
Contact name Jacquetta Trasler
Organization name McGill University
Department Pharmacology & Therapeutics; Human Genetics
Lab RI-MUHC; CHHD Program
Street address 1001 Decarie Boul, Block E, ES1.4380
City Montreal
State/province Quebec
ZIP/Postal code H4A 3J1
Country Canada
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (21)
GSM5075949 Wt_G1_3-9-G
GSM5075950 Wt_G2_L13-C
GSM5075951 Wt_G2_L14C
BioProject PRJNA701304
SRA SRP305736

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Supplementary file Size Download File type/resource
GSE166586_RAW.tar 442.6 Mb (http)(custom) TAR (of TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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