Geneticists Discover Maternal Proteins with Epigenetic Influence Over Fetal Development

By Brittany Wade 

September 8, 2022 | Recent discoveries from Walter and Eliza Hall Institute (WEHI) researchers demonstrated that epigenetic information not only passes from mother to child but has lasting effects on development and growth. 

Epigenetics is the study of how external forces (i.e., diet, physical activity, environmental conditions, etc.) affect gene expression without altering the genetic sequence. It determines which genes turn “on” and “off,” ultimately regulating cellular, organ, and systemic function. 

Historically, scientists assumed little epigenetic information passed through the germline due to the “factory reset” that occurs shortly after conception. A reset involves inherited epigenetic controls that fall away from the zygote’s DNA to make room for a fresh start. However, according to WEHI scientists and their colleague Edwina McGlinn, Monash University and The Australian Regenerative Medicine Institute associate professor, epigenetic inheritance is more prevalent than once believed. 

"It took us a while to process because our discovery was unexpected," said Professor Blewitt, WEHI Epigenetics and Development Division joint head and chief investigator professor, in a press release. "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. It could open a Pandora's box as to what other epigenetic information is being inherited." 

Published in Nature Communications (DOI: 10.1038/s41467-022-32057-x), the WEHI team discovered that maternal epigenetic controls—inherited from oocyte to zygote in mice—have a significant impact on fetal development. The study focused on a protein called SMCHD1—identified by Blewitt in 2008—which controls Hox gene expression. Hox genes exist in every animal, from flies to humans, orchestrating skeletal patterning and influencing development along the anterior-posterior axis.  

SMCHD1 binds and silences Hox genes, preventing overexpression and unfavorable transformations in the spine. Under healthy conditions, Hox genes are only expressed at specific intervals and in particular cells, with SMCHD1 regulating their expression post-implantation. 

The gene that codes for SMCHD1, structural maintenance of chromosomes hinge domain containing 1 or Smchd1, is a maternal effect gene that regulates healthy offspring development. The team focused on SMCHD1 because it does not incite embryonic death upon deletion, making it a prime candidate for epigenetic study. 

"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," said Natalia Benetti, first author and WEHI Epigenetics and Development Ph.D. candidate. "Knowing this is also happening to a set of essential genes that have been evolutionarily conserved from flies through to humans is fascinating." 

When the team removed SMCHD1 from mouse eggs, the mice born from those eggs had “an altered skeleton” and disrupted vertebrae. “This could only be explained by an epigenetic change due to the loss of SMCHD1 in the egg,” wrote Blewitt and Benetti in a recent article for The Conversation, a nonprofit, independent news organization. 

The study suggests that even if a mouse does not directly inherit a gene from its mother, that gene—or the absence thereof—can still affect development throughout the offspring’s lifespan. 

A Pandora’s Box of Questions 

The highest degree of epigenetic change occurs during the “factory reset” of early embryonic development. Since offspring are the most vulnerable to any embryonic change during this time, the team asserts that geneticists and developmental scientists could benefit from studying inherited epigenetic controls more closely.  

For example, human SMCHD1 variants show associations with diseases like muscular dystrophy. If the team’s findings prove relevant to humans, SMCHD1, and other proteins like it, could serve as a new drug target to help patients fight debilitating diseases in utero.

For now, there are still more questions than answers. What if maternal protein composition was only one of many inherited epigenetic factors orchestrating fetal growth? Perhaps a mother’s nutrient profile and activity level also control gene expression. What if paternal protein content plays a more significant role than anticipated? If epigenetic controls are inheritable, what effects do they have over multiple generations? The team hopes to one day answer these questions and more; however, one thing is certain: we inherit much more from our parents than we think.