WEHI researchers have made a discovery about embryonic development that could provide new clues to understanding and treating developmental and degenerative disorders.

The research team was led by Dr Iromi Wanigasuriya, Dr Quentin Gouil and Professor Marnie Blewitt, together with colleagues from the University of Newcastle and Monash Biomedicine Discovery Institute.

“Proteins found within the egg (that we get from our mum) ensure correct gene expression during early embryo development and have both long and short-term impacts on the health of the embryo,” Dr Wanigasuriya said.

“We discovered that a protein called SMCHD1 is one such factor whose maternal supply is crucial for mouse embryonic gene expression.”

Imprinted genes

Some genes behave differently in offspring, depending on whether they are inherited from the mother or the father. This phenomenon, called ‘genomic imprinting’, is essential for healthy development. Compromised genomic imprinting leads to developmental diseases.

“When a sperm fertilises an egg, both cells’ DNA carries ‘epigenetic marks’ from the parent to the child. These marks impact how the genes can be used and, in some cases, have been linked to long-term health impacts,” Dr Wanigasuriya said.

The team used advanced microscopy to show that maternal SMCHD1 proteins persisted within embryos for at least five cell divisions.

“Using powerful new genomic analysis techniques, we were able to identify ten genes that were switched off by maternal SMCHD1 in the early embryo. This is the first time SMCHD1 from the egg has been identified as having a role in imprinting,” Dr Gouil said.

“The mother’s SMCHD1 altered the imprinted gene expression – potentially leaving a lasting legacy in the offspring.”

SMCHD1 and disease

Professor Blewitt has been studying the SMCHD1 protein and its role in development and disease since she first discovered it in 2008. She said her team’s new discovery helped to explain recently discovered roles of SMCHD1 in developmental disorders such as Prader-Willi Syndrome (PWS) and Bosma arhinia microphthalmia syndrome (BAMS), as well as facioscapulohumeral muscular dystrophy (FSHD), a form of muscular dystrophy.

“Studying SMCHD1 in early embryos has uncovered new gene targets that this protein silences and could explain how changes in SMCHD1 activity contribute to disease,” Professor Blewitt said.

“We are currently leading a proprietary drug discovery effort at WEHI to leverage our knowledge around SMCHD1 and design novel therapies to treat developmental and degenerative disorders. This research broadens our understanding of how these novel drug candidates might impact gene expression.”