The genome-which contains genes encoded in DNA-acts as the fundamental blueprint of life. But what you might not know is that, in addition to this genetic information, we have something akin to an "instruction manual" for how genes should be handled. This instruction manual is known as the epigenome. Azusa Inoue, Team Director of the Laboratory for Epigenome Inheritance at the RIKEN Center for Integrative Medical Science, is investigating how the epigenome behaves during the creation of egg cells, or oocytes. Recent studies have revealed that the epigenome of the oocyte plays important roles in the development of the fetus and the placenta following fertilization, as well as in maintaining pregnancy. We spoke with Dr. Inoue about this "wisdom of life"-knowledge encoded in the epigenome that may help us understand how organisms develop from birth to growth and aging.
Azusa Inoue, Team Director, Laboratory for Epigenome Inheritance, RIKEN Center for Integrative Medical Sciences © 2026 RIKEN
Early interest in the fertilized egg
The concept of the epigenome (Fig.1) was proposed in the 1940s, to solve a fundamental problem in development: how can a single fertilized egg, containing essentially the same genetic information in every descendant cell, develop into an organism containing many radically different kinds of cells? The prefix epi- means "upon" or "in addition to," and is used to refer to information added to the genetic information encoded in the genome. This information takes the form of chemical modifications attached to DNA or to proteins associated with the DNA. Epigenetics has attracted considerable attention as a field of research with potential applications in understanding disease mechanisms and developing new therapies and drugs.
Figure 1. What is the epigenome? The epigenome is primarily regulated through two mechanisms: DNA methylation, in which methyl groups are added to specific regions of DNA, and histone modification, in which chemical modifications are added to histone proteins around which DNA is wrapped. © 2026 RIKEN
"Originally, I wanted to understand how a huge and complex organism could develop from a single cell-the fertilized egg," says Inoue.
The cells that make up our bodies include many specialized cell types-neurons and muscle cells, for example-which differentiate based on the blueprint coded in DNA. Yet when two highly differentiated germ cells, typically an oocyte and a sperm, fuse at fertilization to form a zygote-the single cell that becomes the organism-the resulting cell acquires totipotency, the ability to differentiate into any cell type. For this to happen, some form of "resetting" must occur. It was once thought that the epigenomes of both the oocyte and sperm would likewise be reset.
"Both the oocyte and sperm undergo epigenetic reprogramming after fertilization, but they are not completely reset to a blank slate. Some portions of the epigenome escape this reprogramming and are transmitted to the next generation."
In 2017, Inoue discovered a previously unknown oocyte-derived epigenomic feature that escapes post-fertilization reprogramming in mammals.
"Acquired factors that we encounter throughout life, such as our developmental environment, generally do not alter the DNA sequence itself. However, epigenetic marks-the chemical modifications added to DNA and its associated proteins-can potentially be altered by acquired factors such as lifestyle and environmental influences. What is fascinating here is that it is possible that phenomena resembling inheritance can actually occur without changes to the genome. I wanted to explore that possibility in greater depth."
Micromanipulation is performed using mouse eggs. Microscopes are indispensable for research aimed at elucidating the mechanisms of reproduction and development. © 2026 RIKEN
Focusing on histone modifications
The epigenome involves two major mechanisms. One is DNA methylation, which means the addition of methyl groups to specific regions of DNA. The other is histone modification, in which chemical modifications are added to proteins called histones, around which DNA is wrapped. Inoue's research focuses primarily on the second mechanism.
One modification that attracted his attention is known as "H3K27me3," a bit of a mouthful. This histone modification is associated with the repression of gene activity. In his 2017 work, he demonstrated that it is a mark that can be transmitted to the next generation.
"We have shown that this epigenomic mark plays an important role in embryonic development and placental formation. Now, I wanted to understand why it has these functions. I also wanted to know how it became established in the oocyte in the first place."
Analyzing oocyte growth with world-class precision
To understand how it is established, the team began to track key histone modifications as mouse oocytes grew and matured. The team had previously discovered that establishment of H3K27me3 first requires another modification called H2Aub. Working with samples of just 100 or so cells, they mapped these molecular marks with high sensitivity. A clear sequence emerged: H2Aub and an activating mark, known as H3K4me3 appeared first, with H3K27me3 following later.
"That timing turned out to be the key clue," Inoue says. "It is difficult for H3K27me3 to be established on genes that are already active." Seeing this, the team proposed that H2Aub first quiets active genes, creating the conditions needed for H3K27me3 to take hold.
A balancing act
The researchers tested this idea by removing the epigenetic marks one by one. Without H2Aub, activating signals dominated and H3K27me3 failed to form. When the activating mark was also removed, H3K27me3 returned. "It is really a matter of balance," Inoue explains. "When the repressive state gains the upper hand, H3K27me3 can be established, but when activation dominates, it is lost." (Fig. 2)
Figure 2: A genetic balance governing epigenome establishment. H2Aub functions to repress gene expression ("off"), whereas H3K4me3 promotes gene activation ("on"). When the repressive state predominates, H3K27me3 is established, while when the active state predominates, it is lost. © 2026 RIKEN
A message that lasts beyond fertilization
The story did not end in the egg. The group discovered that after fertilization, embryos lacking oocyte-derived H3K27me3 developed unusually large placentas, while those with the mark formed normal ones. It seems, then, that the inherited mark keeps placental growth genes under control during early development. Without it, those genes become overactive and the placenta experiences excessing growth. "This could potentially place an additional burden on the mother," Inoue explains.
"What fascinates me is that the oocyte prepares information that will only matter much later, after fertilization," Inoue says. "It is as if the egg carries forward a quiet piece of biological wisdom."
"It may be," says Inoue, "that women protect themselves-the maternal organism-by incorporating into their oocytes an epigenomic program that limits excessive placental growth, thereby preventing an excessive burden during a future pregnancy. The oocyte, of course, has no way of knowing that part of itself will eventually become the placenta, yet it prepares its epigenome as though it were anticipating events years into the future. Isn't that remarkable? These are cells without a brain, yet I cannot help feeling that they seem to be thinking about something."
These findings come from mice, and whether the same mechanism operates in humans remains an open question. Similar strategies may exist in plants, where the endosperm plays a role comparable in some respects to the mammalian placenta.
"I started this research simply because I wanted to understand the fertilized egg," Inoue says. "I never expected it to lead here, and that is what keeps it exciting."
This article is a translation of the Japanese article "卵子のエピゲノムに託された生命の知恵".
Azusa Inoue explains epigenome using a model of histones that he received from his mentor. © 2026 RIKEN
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About the researcher
Azusa Inoue is Team Director at Laboratory for Epigenome Inheritance, RIKEN Center for Integrative Medical Sciences (IMS), where he leads research at the intersection of reproductive biology and developmental science. He joined RIKEN IMS in 2018 as a YCI/Senior Scientist and served as Team Leader from 2022 to 2025. He has also been a Visiting Associate Professor at Tokyo Metropolitan University since 2019. Before joining RIKEN, he spent six years as a Postdoctoral Fellow and Research Specialist at Harvard Medical School and Boston Children's Hospital, following a postdoctoral position at the University of North Carolina at Chapel Hill. He received his Ph.D. from the University of Tokyo's Graduate School of Frontier Sciences in 2011 and his Bachelor's degree from Tokyo Metropolitan University in 2006. His passion lies in understanding the science of life, with a particular interest in oocytes and reproductive biology. Outside the lab, he enjoys spending time with kids-combining curiosity, science, and fun.
