Genome-wide profiling of the epigenetic landscape of histone variant TH2B in murine oocytes and pre-implantation embryos

In brief This study investigates the role of TH2B in pre-implantation embryos and found that TH2B deposition varies between gametes but rapidly redistributes in two-cell embryos after fertilization. Our ultra-low-input native chromatin immunoprecipitation and sequencing (ULI-NChIP-seq) revealed that TH2B is enriched in early chromatin but decreases after the two-cell stage, with strong correlations to key regulatory regions, histone modifications and transposable elements (TEs), indicating its critical role in zygotic genome activation and early developmental processes. Abstract The histone variant TH2B, enriched in oocytes, sperm and early embryos, decreases as embryos differentiate into pre-gastrula stages. Despite its presence, the role of TH2B in epigenetic reprogramming during early embryonic development remains largely under-researched. Our study employed ULI-NChIP-seq to analyze the genome-wide distribution of TH2B in metaphase II (MII) oocytes and early embryos. We found that TH2B is enriched in the chromatin of oocytes and two-cell stage embryos but becomes less prevalent after the two-cell stage. Correlation analysis revealed that the TH2B chromatin patterns in sperm and pre-implantation embryos are more similar to each other than to those in MII oocytes. Gene ontology (GO) analysis of TH2B-occupied loci linked them to various developmental processes including oogenesis, fertilization, chromatin modification and transcription regulation. The study also identified a strong association of TH2B with specific TEs, particularly long terminal repeats, which are known to regulate pre-implantation development. Additionally, early embryos showed H3K9me3 marks at TH2B-bound loci. TH2B exhibited strong correlations with H2A.Z and H3.3 in the two-cell and eight-cell stages, a positive association with H3K27Ac and H3K4me3 and a negative correlation with H3K27me3. Allelic reprogramming analysis of TH2B in embryos from C57BL/6J and DBA/2J crosses revealed differential dynamics between maternal and paternal alleles, with a notable paternal bias at the promoter in two-cell embryos. Thus, TH2B’s enrichment in early embryonic stages and its association with key regulatory regions and histone modifications underscore its importance in zygotic genome activation and subsequent developmental processes.