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How DNA is packaged orchestrates development
New research on zebrafish embryos illustrates how the early embryo creates all the cell types needed for an adult zebrafish. Zebrafish embryos are used as a model system for human embryos as we share significant developmental similarities.
Researchers from Huntsman Cancer Institute (HCI) at the University of Utah (U of U) demonstrate how hundreds of genes controlling embryo development are uniquely packaged into an early embryo - tracking influences as far back as the DNA packaging of sperm. Packaging controls how, when, and where different genes are expressed in the embryo. Findings, published in Cell, provide a mechanism for how parental packaging of genes impacts offspring.
Brad Cairns PhD, Senior Director of Basic Science, and Professor and Chair of Oncological Sciences at U of U, along with his colleagues observed how genes in the nucleus turn 'on' (functioning mode) and 'off' (non-functioning mode) at different stages in development. The physical compression of DNA through 'packaging' is needed to make DNA strands fit within a cell nucleus. But, this compression also affects how genes get expressed (function) based on how tightly packaging makes genes inaccessible to being read.
Researchers have long wanted to know (1) if and how genes from mom and dad might be packaged in a manner that influences their expression (function), while influencing continued development of the embryo; and then, (2) how are those packaging states maintained or are they reprogrammed continually throughout the developmental process.
"A key question in embryonic development is how the early embryo achieves the state of totipotency - that is, an ability to become any type of cell in the body. We reasoned that the central answer might be to package all the decision-making genes in a special physical state that helps identify and regulate them."
The study identified one packaging histone - histone variant H2AFV - clearly acting as a mechanism for gene packaging. Remarkably, although the initial packaging of genes in the paternal sperm differs somewhat from packaging in the maternal egg, the study also revealed maternal packaging reprograms to the same packaging state as the paternal genome, harmonizing the packaging states of both parents.
This implies H2AFV may be the mechanism for how even environmental factors - epigenetic influences such as smoking - might get swept into H2AFV and its 'harmonizing' influence to be packaged as new traits.
"These packaging states help define whether and how genes are expressed in normal development. Such genes, if misregulated, can lead to developmental disorders and perhaps to a predisposition for cancer."
• Distinct nucleosomes occupy all hypomethylated DNA in zebrafish sperm and early embryos
• These Placeholder nucleosomes bear H3K4me and the histone variant H2A.Z(FV)
• Upon genome activation, Placeholders become active or poised nucleosomes
• Placeholder localization excludes DNA methyla and regulates embryonic transcription
The fate and function of epigenetic marks during the germline-to-embryo transition is a key issue in developmental biology, with relevance to stem cell programming and transgenerational inheritance. In zebrafish, DNA methylation patterns are programmed in transcriptionally quiescent cleavage embryos; paternally inherited patterns are maintained, whereas maternal patterns are reprogrammed to match the paternal. Here, we provide the mechanism by demonstrating that “Placeholder” nucleosomes, containing histone H2A variant H2A.Z(FV) and H3K4me1, virtually occupy all regions lacking DNA methylation in both sperm and cleavage embryos and reside at promoters encoding housekeeping and early embryonic transcription factors. Upon genome-wide transcriptional onset, genes with Placeholder become either active (H3K4me3) or silent (H3K4me3/K27me3). Notably, perturbations causing Placeholder loss confer DNA methylation accumulation, whereas acquisition/expansion of Placeholder confers DNA hypomethylation and improper gene activation. Thus, during transcriptionally quiescent gametic and embryonic stages, an H2A.Z(FV)/H3K4me1-containing Placeholder nucleosome deters DNA methylation, poising parental genes for either gene-specific activation or facultative repression.
Authors: Patrick J. Murphy, Shan Fu Wu, Cody R. James, Candice L. Wike, Bradley R. Cairns
Keywords: DNA methylation, zebrafish, H2A.Z, germline-to-embryo transition, zygotic genome activation
The work was supported by the National Institutes of Health/National Cancer Institute P30 CA24014, National Institutes of Health T32HD007491, the Howard Hughes Medical Institute, and the Huntsman Cancer Foundation.
Huntsman Cancer Institute (HCI) at the University of Utah is the official cancer center of Utah. The cancer campus includes a state-of-the-art cancer specialty hospital as well as two buildings dedicated to cancer research. HCI treats patients with all forms of cancer and operates several clinics that focus on patients with a family history of cancer. As the only National Cancer Institute (NCI)-Designated Comprehensive Cancer Center in the Mountain West, HCI serves the largest geographic region in the country, drawing patients from Utah, Nevada, Idaho, Wyoming, and Montana. HCI scientists have identified more genes for inherited cancers than any other cancer center in the world, including genes responsible for hereditary breast, ovarian, colon, head, and neck cancers, along with melanoma. HCI manages the Utah Population Database - the largest genetic database in the world, with information on more than 9 million people linked to genealogies, health records, and vital statistics. The institute was founded by Jon M. and Karen Huntsman.
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Histone H2A.V is a protein that in humans is encoded by the H2AFV gene. Image credit: Wikipedia