A study on epigenetic genetics at the RIKEN Center for Integrative Medical Sciences showed that in mouse egg cells, modifications to the H2A histone in lysine 119 laid the basis for functional modifications inherited from the DNA of the mother.
In books and movies, a group of people on a special mission always sends a scout to do a survey before moving forward. Sometimes, scouts leave signs or signs that let the group know where to go. Researchers led by Azusa Inoue at the RIKEN Center for Integrative Medical Sciences in Japan discovered a marker left behind in unfertilized egg cells that identifies the DNA modifications that would be inherited if the egg was fertilized. Specifically, they found that without initial modifications of the H2A histone in lysine 119 – technically called H2AK119ub1 – the genetic modifications would not occur later. When development is permitted, one of the consequences of this deficit has been an enlargement of the placenta after implantation of the embryo. This study was published in Natural Genetics On April 5th.
For many years we have been learning in school that the acquired traits are not inherited. To some extent, this was true. Tightening your neck too much to get food will not produce babies with longer necks. However, the function of your DNA can be modified throughout your life. For example, the DNA structure of chromosomes is supported by proteins called histones. When histones are modified, they can change the way genes are expressed in the body. This is the science of epigenetics, and a previous study by Inoue and colleagues showed that the acquired triple-methyl of the H3 histone in lysine 27 (abbreviated to H3K27me3) in mammalian egg cells can be inherited. In the new study, the team used a technique called low-input CUT & RUN to start answering the question of how this might happen.
First, the researchers examined the timing of the two different histone modifications. They found that each gene displaying H3K27me3 also showed H2AK119ub1 in rat egg cells. To suspect its importance, the researchers flushed out two types of proteins that make up H2AK119ub1 in oocytes. Low-input CUT & RUN showed that segregated oocytes contained significantly less H3K27me3 than controls in a subset of genes that would normally bring H3K27me3 to the next generation. Thus, H2AK119ub1 acts as a kind of marker left by the flashlight, and defines where the next H3K27me3 should follow. “We discovered that H2AK119ub1 is necessary for maternal inheritance of H3K27me3, making the H2AK119ub1-H3K27me3 pathway a major player in epigenetic inheritance across generations in mammals,” says Inoue.
Then the researchers found something they hadn’t expected. The test showed that the loss of H3K27me3 itself is inherited by the fertilized embryos, and is not reversible. Moreover, this deficiency resulted in increased mortality, miscarriage, and placental enlargement. “It was surprising to find that defects in oocyst histone modification are irreversibly inherited by embryos and cause long-term consequences in development,” says Eno.
Thus the results showed that despite normal DNA in the mouse egg cell, if the correct instructions – first H2AK119ub1 and then H3K27me3 modifications – were missing, miscarriages and placental hyperplasia could occur. These results have clinical implications, especially for reproductive medicine and placenta defects. “The next step is to find out if any diseases or surrounding environments can affect histone modification,” says Inoue.
Mei H, Kozuka C, Hayashi R, Kumon M, Koseki H, Inoue A (2021) H2AK119ub1 guides the maternal genetics and pollen deposition of H3K27me3 in mouse embryos. Nat. Genet. Doi: 10.1038 / s41588-021-00820-3