After coming up against an impassable obstacle, researchers often need to hold their place in one research line and open up another to explore new investigational avenues and uncover new and unexpected findings. The study of epigenetics during fertilization and the early development of human embryos remains a challenging task on multiple levels, thus making researchers hold their place in human research and turn to handy model animals such as the zebrafish (Danio rerio).
However, the mechanisms in zebrafish embryos that promote the selective maintenance of paternally inherited DNA methylation patterns (from the sperm) and reprogramming of maternal patterns (from the oocyte) remain relatively unknown. That is, until the lab the lab of Bradley R. Cairns (Huntsman Cancer Institute, University of Utah, USA) came along with their new study in zebrafish.
In their latest report, the talented team now demonstrates that establishing unmethylated DNA sequences in the genome of sperm and the early embryo, as well as controlling the gene expression programs required for the progression of embryonic development, involves a newly discovered “Placeholder” nucleosome containing histone H2A variant (H2A.Z) and H3K4me1.
The precise particulars of this pristine new paper on Placeholder nucleosomes include:
- Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) assessing levels of promoter-associated features (H3K4me3, H3K27me3, H3K14ac, and H2A.Z) and enhancer-associated features (H3K4me1 and H3K27ac) in zebrafish sperm and early embryos established that Placeholder nucleosomes occupy genomic regions lacking DNA methylation
- Interestingly, these regions represent promoter sequences for genes controlling embryonic development, such as housekeeping genes and early embryonic transcription factor genes
- Using engineered gene knock-out zebrafish, the authors discovered that the Anp32e chaperone, which controls H2A.Z occupancy in the genome, acts to prevent unwanted transcription events and ensure the precise execution of transcriptional programs
- Additionally, Placeholder nucleosomes reprogram the maternal genome to match that of the sperm, allowing epigenetic synchronization of the embryo and developmental progress
- Following the activation of genome-wide transcription during embryo development, Placeholder-marked regions resolve to either transcriptionally active H3K4me3-modified chromatin or a transcriptionally poised bivalent state marked by H3K4me3 and H3K27me3
- The authors suspect that this mechanism orchestrates embryonic development via the synchronized expression or silencing of crucial genes
- Gain-of-function/loss-of-function approaches also established that the loss of Placeholder function led to DNA methylation accumulation, whereas more widespread Placeholder function promoted the expansion of DNA hypomethylation and unwanted gene activation
But what does this new scientific progress mean in the bigger picture? “The implications of this work include a possible mechanism for how environmental factors — for example, smoking — might influence inheritance of traits, by affecting how developmental genes are packaged. These packaging states help to define whether and how genes are expressed in normal development. Such genes, if misregulated can lead to developmental disorders, and perhaps to predisposition for cancer,” says study leader Cairns. “By better understanding what happens in normal development, it opens up new possibilities for being able to identify the precursors to diseases like cancer, when cell development goes haywire.”
So, hold your place in the paper you were pondering over, and see all the progress and peruse this unparalleled piece on Placeholder nucleosomes at Cell, January 2018!