Dynamic mRNA degradome analyses indicate a role of histone H3K4 trimethylation in association with meiosis-coupled mRNA decay in oocyte aging

Abstract

A decrease in oocyte developmental potential is a major obstacle for successful pregnancy in women of advanced age. However, the age-related epigenetic modifications associated with dynamic transcriptome changes, particularly meiotic maturation-coupled mRNA clearance, have not been adequately characterized in human oocytes. This study demonstrates a decreased storage of transcripts encoding key factors regulating the maternal mRNA degradome in fully grown oocytes of women of advanced age. A similar defect in meiotic maturation-triggered mRNA clearance is also detected in aged mouse oocytes. Mechanistically, the epigenetic and cytoplasmic aspects of oocyte maturation are synchronized in both the normal development and aging processes. The level of histone H3K4 trimethylation (H3K4me3) is high in fully grown mouse and human oocytes derived from young females but decreased during aging due to the decreased expression of epigenetic factors responsible for H3K4me3 accumulation. Oocyte-specific knockout of the gene encoding CxxC-finger protein 1 (CXXC1), a DNA-binding subunit of SETD1 methyltransferase, causes ooplasm changes associated with accelerated aging and impaired maternal mRNA translation and degradation. These results suggest that a network of CXXC1-maintained H3K4me3, in association with mRNA decay competence, sets a timer for oocyte deterioration and plays a role in oocyte aging in both mouse and human oocytes.

Epigenetic reprogramming during the maternal‐to‐zygotic transition

“…96,97 In contrast, the depletion of CXXC1 causes a marked decrease of H3K4me3 level, regardless of canonical and noncanon-ical peaks. [96][97][98][99][100] ChIP-Seq results further indicated that CXXC1 is essential for the establishment of H3K4me3 in promoter regions modified by H3K4me3 exclusively, whereas KMT2B is required for regions also occupied by H3K27me3. 96 Correspondingly, global transcription activity is downregulated after Cxxc1-maternal deletion, including the genes correlated with mRNA synthesis, translation, and degradation.…”

“…Similar to SETDB1, maternal CXXC1 is essential for oocyte maturation and embryo developmental after fertilization 96,97 . In contrast, the depletion of CXXC1 causes a marked decrease of H3K4me3 level, regardless of canonical and noncanonical peaks 96–100 . ChIP‐Seq results further indicated that CXXC1 is essential for the establishment of H3K4me3 in promoter regions modified by H3K4me3 exclusively, whereas KMT2B is required for regions also occupied by H3K27me3 96 .…”

“…ChIP‐Seq results further indicated that CXXC1 is essential for the establishment of H3K4me3 in promoter regions modified by H3K4me3 exclusively, whereas KMT2B is required for regions also occupied by H3K27me3 96 . Correspondingly, global transcription activity is downregulated after Cxxc1 ‐maternal deletion, including the genes correlated with mRNA synthesis, translation, and degradation 98,100 . Particularly, impaired translation of transcripts encoding maternal factors (like Btg4 ) important for maternal mRNA decay further prevented the maternal mRNAs degradation in mouse CXXC1 null oocytes and zygotes 98,100 …”

“…98,100 Particularly, impaired translation of transcripts encoding maternal factors (like Btg4) important for maternal mRNA decay further prevented the maternal mRNAs degradation in mouse CXXC1 null oocytes and zygotes. 98,100…”

“…Correspondingly, global transcription activity is downregulated after Cxxc1 ‐maternal deletion, including the genes correlated with mRNA synthesis, translation, and degradation 98,100 . Particularly, impaired translation of transcripts encoding maternal factors (like Btg4 ) important for maternal mRNA decay further prevented the maternal mRNAs degradation in mouse CXXC1 null oocytes and zygotes 98,100 …”