Gene Silencing Mechanism Linked to PWS Focus of Early Study

The maternal SMCHD1 protein ensures genomic imprinting and the effective silencing of particular genes by protecting them from “gene-activating” proteins in the fertilized egg cell (or oocyte), according to a study in mice.

Since SMCHD1’s gene silencing effects are known to contribute to Prader-Willi syndrome (PWS), these findings may help to identify new targets and therapeutic approaches for PWS, its researchers said.

The study, “Smchd1 is a maternal effect gene required for genomic imprinting,” was published in the journal eLife.

Each person has 46 chromosomes — rodlike structures where genes are located — arranged in 23 pairs, with one chromosome inherited from the mother and the other from the father.

While both parental and maternal gene copies are often used, the activity of some genes and chromosomal regions depend entirely on the copy from only one parent.

Genomic imprinting is the process by either the maternal or the paternal copy is silenced, or “turned off,” by chemical tags (epigenetic marks) added to DNA or histones — the proteins that pack DNA — without affecting the genetic code.

“When a sperm fertilizes an egg, both cells’ DNA carries epigenetic marks from the parent to the child, which in some cases have been linked to long-term health impacts,” Iromi Wanigasuriya, the study’s lead author and a PhD student at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Australia, said in a press release.

“It is known that proteins found within the egg (proteins that we get from our mum) help to protect these imprinted genes during early embryo development,” she added.

PWS is most commonly caused by genetic alterations that lead to the loss of function of paternal genes located on chromosome 15, which control metabolism, appetite, growth, intellectual function, and social behavior.

Due to genomic imprinting and silencing of this region — known as the PWS locus — in the maternally inherited-chromosome 15, defects in the paternal gene copies cannot be compensated by healthy ones inherited from the mother.

PWS also may be caused by inheriting two chromosome 15s from the mother, both of which are shut down in the PWS locus, or by an imprinting defect that turns off the parental PWS locus.

As such, reactivating these silenced genes may be a way of treating the disease.

Previous studies showed that SMCHD1 — a protein involved in epigenetics and gene silencing — turns off PWS-related genes and that SMCHD1’s loss restores gene activity.

Wanigasuriya and colleagues at WEHI and other Australian institutions evaluated whether “a mother’s SMCHD1 protein could be transferred into a newly formed embryo, and how this impacted the expression [activity] of imprinted genes,” Wanigasuriya said.

Applying genomic analysis techniques to mouse eggs and embryos, they showed for the first time that maternal SMCHD1 silenced 10 genes in the early embryo.

Quentin Gouil, PhD, one of the study’s authors, said this work revealed a critical time window in early embryonic development during which the mother’s SMCHD1 silences target genes.

“While the effects we discovered were subtle, we know that events occurring in early embryonic development can have long-term effects on health. As well as extending our understanding of genomic imprinting, this research adds an extra dimension to the many ways we know parents can impact their offspring’s health,” Gouil added.

Interestingly, some maternal SMCHD1 target genes were distinct from those of the egg-derived protein, which included PWS-associated genes.

The researchers also found a dose-dependent effect of egg-derived SMCHD1 in regulating gene silencing in several gene clusters, including the PWS locus, and that both maternal and egg-derived SMCHD1 can control imprinting of some genes.

Further analyses suggested that SMCHD1 ensures that specific epigenetic marks in histones effectively result in gene silencing by “preventing the action of … epigenetic activators via an insulating [protective] mechanism,” the researchers wrote.

Marnie Blewitt, PhD, the study’s senior author, said that “studying SMCHD1 in early embryos has uncovered new gene targets that this protein silences,” and that “this could explain how changes in SMCHD1 activity contribute to diseases.”

Besides PWS, SMCHD1 has also been implicated in facioscapulohumeral muscular dystrophy and Bosma arhinia and microphthalmia.

“We are currently leading a proprietary [therapy] discovery effort at WEHI to leverage our knowledge around SMCHD1 and design novel therapies to treat developmental and degenerative disorders,” Blewitt said.

“This research broadens our understanding of how these novel [therapy] candidates might impact gene expression,” Blewitt added.