How maternal genes give control to embryonic genes
After fertilization, embryo development must shift from maternal proteins to early embryo or zygote proteins. This is called the maternal-to-zygotic transition (MZT), a step still not fully understood. Existing technology isn't sensitive enough to pick up everything happening in a zygote. But, a new technique now exists to map epigenetic DNA changes.
Epigenetic marks help regulate how genes are expressed, or read, to produce proteins. Bing Ren and Arne Klungland of the University of Oslo, have led new research unraveling the earliest stages of MZT. Their new technique is called μChIP-seq, and may also impact cancer research.
Their research was published September 14 in the journal Nature.
The improved sensitivity of μChIP-seq, was developed jointly by Arne Klugland, Bing Ren and John Arne-Dahl of Oslo University. According to Ren, its development led to “some remarkable discoveries completely changing our view of epigenetic inheritance mechanisms.”
Ren and colleagues used μChIP-seq to investigate epigenetic control in MZT, examining how mouse embryos distribute the H3K4me3 mark. Comparing H3K4me3 distribution in many mouse zygotes they found the unexpected — broad and distinct areas of the zygote genome, some 22%, is heavily marked with H3K4me3. These domains rapidly decrease in size over early development to eventually shrink to only 1% to 2% of the fetal genome.
H3K4me3 is known to be critical in regulating MZT. It modifies chromatin, the tightly wrapped complex of DNA and proteins nestled within the nucleus.
H3K4me3 adds three identical molecules — a methyl group — to histone 3. Histones coil DNA around them restricting expression of proteins and condensing a DNA strand to fit within the nucleus.
John Arne-Dahl fine tuned the mapping technique so that only a few hundred embryos or cells were needed for each experiment. Previous mapping techniques required up to 10,000 cells for similar experiments. Inkyung Jung, co-first author and a Ludwig postdoc in Ren’s lab, contributed significantly to the analysis of the data that was collected.
“The key lesson we learned: genes destined to be turned on specifically in the fertilized egg are covered by this unique chromatin structure — H3K4me3.
“H3K4me3 is how the oocyte influences which genes in the zygote become active. It is an epigenetic mechanism for passing information from the maternal oocyte to the zygote.”
Bing Ren PhD, Ludwig Institute for Cancer Research, La Jolla, California; Department of Cellular and Molecular Medicine, University of California, Moores Cancer Center, San Diego School of Medicine, California, USA
In fact, releasing the H3K4me3 mark by specialized enzymes activates reading of the zygote genome, thus allowng it to produce new proteins of its own, not strictly those of the mother.
The scientists ability to map “epigenomes” using such a small number of cells will be valuable to cancer research as the epigenetic landscape is dramatically rearranged in cancers, driven by small subpopulations of cells in situations of drug resistance and metastasis.
Ren: “With a better understanding of the epigenetic landscapes in cancers, we are going to need more tools to study the basis of tumorigenesis. We have a long way to go, but our goal is to have a thorough understanding of gene regulatory programs, and use that knowledge to treat cancer and develop more diagnostic tools.”
Maternal-to-zygotic transition (MZT) is essential for the formation of a new individual, but is still poorly understood despite recent progress in analysis of gene expression and DNA methylation in early embryogenesis1, 2, 3, 4, 5, 6, 7, 8, 9. Dynamic histone modifications may have important roles in MZT10, 11, 12, 13, but direct measurements of chromatin states have been hindered by technical difficulties in profiling histone modifications from small quantities of cells. Recent improvements allow for 500 cell-equivalents of chromatin per reaction, but require 10,000 cells for initial steps14 or require a highly specialized microfluidics device that is not readily available15. We developed a micro-scale chromatin immunoprecipitation and sequencing (μChIP–seq) method, which we used to profile genome-wide histone H3 lysine methylation (H3K4me3) and acetylation (H3K27ac) in mouse immature and metaphase II oocytes and in 2-cell and 8-cell embryos. Notably, we show that ~22% of the oocyte genome is associated with broad H3K4me3 domains that are anti-correlated with DNA methylation. The H3K4me3 signal becomes confined to transcriptional-start-site regions in 2-cell embryos, concomitant with the onset of major zygotic genome activation. Active removal of broad H3K4me3 domains by the lysine demethylases KDM5A and KDM5B is required for normal zygotic genome activation and is essential for early embryo development. Our results provide insight into the onset of the developmental program in mouse embryos and demonstrate a role for broad H3K4me3 domains in MZT.
This research was funded by Ludwig Cancer Research, the American Heart Association, the Oslo University Hospital Early Career Award, the Norwegian Cancer Society, the Anders Jahre Foundation and the Norwegian Research Council.
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested nearly $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.
Return to top of page
Sep 21, 2016 Fetal Timeline Maternal Timeline News News Archive
Epigenetic marks help regulate genes in an embryo. DNA wound tightly around a Histone cannot
be easily accessed and "read" into function. H3K4me3 marks, have to be removed by enzymes
in order to activate the zygote — allowing genes to be read and make proteins.
Image Credit: Nature Genomic architecture, and eras of investigation.