Hierarchical Accumulation of Histone Variant H2A.Z Regulates Transcriptional States and Histone Modifications in Early Mammalian Embryos

Abstract

Early embryos undergo extensive epigenetic reprogramming to achieve gamete‐to‐embryo transition, which involves the loading and removal of histone variant H2A.Z on chromatin. However, how does H2A.Z regulate gene expression and histone modifications during preimplantation development remains unrevealed. Here, by using ultra‐low‐input native chromatin immunoprecipitation and sequencing, the genome‐wide distribution of H2A.Z is delineated in mouse oocytes and early embryos. These landscapes indicate that paternal H2A.Z is removed upon fertilization, followed by unbiased accumulation on parental genomes during zygotic genome activation (ZGA). Remarkably, H2A.Z exhibits hierarchical accumulation as different peak types at promoters: promoters with double H2A.Z peaks are colocalized with H3K4me3 and indicate transcriptional activation; promoters with a single H2A.Z peak are more likely to occupy bivalent marks (H3K4me3+H3K27me3) and indicate development gene suppression; promoters with no H2A.Z accumulation exhibit persisting gene silencing in early embryos. Moreover, H2A.Z depletion changes the enrichment of histone modifications and RNA polymerase II binding at promoters, resulting in abnormal gene expression and developmental arrest during lineage commitment. Furthermore, similar transcription and accumulation patterns between mouse and porcine embryos indicate that a dual role of H2A.Z in regulating the epigenome required for proper gene expression is conserved during mammalian preimplantation development.

CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos

“…The developments of ultra‐low‐input chromatin immunoprecipitation (ChIP; Brind'Amour et al , 2015) and immunocleavage (ChIC; Skene & Henikoff, 2017) sequencing methods have enabled the study of the dynamic reprogramming of different histone modifications and histone variants during mammalian maternal‐to‐zygotic transition (MZT), which revealed diverse reprogramming patterns for H3K4me3 (Dahl et al , 2016; Zhang et al , 2016), H3K27me3 (Liu et al , 2016; Zheng et al , 2016), H3K9me3 (Wang et al , 2018), H3K36me3 (Xu et al , 2019), H2AK119ub1 (Chen et al , 2021; Mei et al , 2021), H3.3 (Ishiuchi et al , 2020) and H2A.Z (Liu et al , 2022). The study of H3K27ac during zebrafish MZT has revealed distinct dynamics between promoters and distal regions (Zhang et al , 2018; Chan et al , 2019; Miao et al , 2022).…”

Multi‐Omics Analysis Reveals Translational Landscapes and Regulations in Mouse and Human Oocyte Aging

“…Epigenetic establishments are also crucial events during oogenesis, oocyte meiotic maturation, OET, and zygotic development. [71,72] Aberrant epigenetic dynamic modifications are associated with decreased female fertility in advanced maternal age. [6,[14][15][16]53,73] Consistent with previous studies, [17,18] we reported the translational repression of DNA methylation factors, including Dnmt1, Dnmt3a/b, and Uhrf1, in aged mouse and human oocytes.…”

Roles of Histone H2A Variants in Cancer Development, Prognosis, and Treatment

“…Heterozygous deletion of H2A.Z is embryonically lethal, underlining its importance in early embryo development [ 64 ]. H2A.Z plays a pivotal role in establishing an intricate pattern of gene expression necessary for proper early development in mammals [ 64 , 65 ]. H2A.Z is highly abundant and enriched in the pericentric heterochromatin of undifferentiated cells like mESCs, but not in differentiated mouse or human cells.…”