Our understanding of early development and its importance for lifelong health is constantly evolving, thanks in part to the growing field of epigenetics. We now know that parents pass along more than just their genes – they also transmit molecular mechanisms that control how genes are expressed. These epigenetic gene regulators help ensure the normal development of a child.
However, only a few genes in our genome carry the epigenetic data of our parents. These “imprinted genes” are either expressed (or not-expressed) based on whether an epigenetic regulator is inherited from the mother or father.
During early embryonic development, certain maternal genes transmit important and lasting epigenetic information from the oocyte (egg cell) to the zygote (fertilized egg). However, outside of this small grouping of imprinted genes, very few other genes have been found to be influenced by the mother’s epigenetic condition – at least until now.
Scientists at the Walter and Eliza Hall Institute (WEHI) of Medical Research in Australia have recently discovered that we may be inheriting more of our mother’s epigenetic information than what was previously thought. In their study, published in Nature Communications, the researchers learned for the first time that a specific protein found in the mother’s egg epigenetically affects the genes required for skeletal patterning in the child.
Principal investigator, professor Marnie Blewitt of WEHI, and her team, which included PhD student Natalia Benetti and Edwina McGlinn of Monash University, were initially surprised by their findings.
“Knowing that epigenetic information from the mother can have effects with life-long consequences for body patterning is exciting, as it suggests this is happening far more than we ever thought, Blewit said. “It could open a Pandora’s box as to what other epigenetic information is being inherited.”
The primary focus of the study was on a protein called SMCHD1, an epigenetic regulator professor Blewit discovered in 2008, and the Hox genes, a group of developmental genes critical for skeletal development.
In developing embryos, Hox genes help lay out the basic skeletal form of the body, and it’s up to an epigenetic regulator to prevent these genes from being activated too early. According to the researchers, the amount of SMCHD1 in the egg determines Hox gene expression, thus instructing the embryo as it develops.
Using a mouse model, when the researchers deleted maternal SMCHD1 from the egg, the offspring were born with altered skeletal structures. However, this modification did not disrupt certain histone marks (H2AK119ub and H3K27me3) from the oocyte in early embryonic development, suggesting that maternal SMCHD1 acts downstream to establish a chromatin state necessary for constant epigenetic silencing and appropriate Hox gene expression later in the growing embryo.
From the data, it was clear to the team that epigenetic information, rather than genetic, passed from the mother to offspring.
Benetti stated, “While we have more than 20,000 genes in our genome, only that rare subset of about 150 imprinted genes and very few others have been shown to carry epigenetic information from one generation to another.”
She emphasized how intriguing it is that a group of essential genes (EG) can also retain maternal epigenetic information, especially since EGs are highly conserved across most species and protected from mutations.
The researchers did point out that maternal SMCHD1 only exists for a few days in the egg after conception. However, while short-lived, the effects are long-lasting because SMCHD1 does not result in embryonic lethality, unlike many maternal effect genes.
Although more research is needed to fully understand the enduring impact of maternal SMCHD1 in the developing embryo, the study does show that this gene is required for proper Hox expression and, thus, normal skeletal patterning.
Rare developmental disorders like FSHD and Bosma arhinia microphthalmia syndrome (BAMS) have been linked with variants in the SMCHD1 gene. Using their newfound knowledge about SMCHD1, the team is currently working on finding ways to develop novel therapies to treat BAMS, FSHD, and similar developmental disorders like Prader-Willi Syndrome.
Overall, the findings from this study increase our understanding not only about maternal SMCHD1, but also on how heritable epigenetic factors influence offspring phenotypes and play a role in human disease.
Source: Natalia Benetti, et al. Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo. Nature Communications, August 2022.
Reference: Not all in the genes: Are we inheriting more than we think? Walter and Eliza Hall Institute. August 12, 2022.