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Department of Physiology, Development and Neuroscience

The soft mechanical signature of glial scars in the central nervous system

Gene expression changes are linked to increased risk for spina bifida, heart defects, and placental abnormalities

Folic acid deficiency adversely affects pregnancy. A study out today reveals that a mutation in a gene necessary for breaking down folic acid in the cell not only disrupts the sperm epigenome but can also alter related gene expression in their grandprogeny. The new research, which also explores how diseases are inherited due to environmental stressors rather than genetic mutations, was published today in the journal Nature Communications.

It was established decades ago that folic acid deficiency causes spina bifida and other congenital malformations. In response, folic acid fortification of cereal products is required in many countries including Canada and the USA. Even so, little is known about the molecular mechanism of folic acid during development.

Previous research by Dr Erica Watson from the Department of Physiology, Development and Neuroscience at the University of Cambridge first showed that this mutation in the Mtrr gene causes metabolic changes in mice similar to folic acid deficiency in humans and also detrimental effects on the development of the great grandprogeny. These defects occur even though the great grandprogeny themselves do not carry the Mtrr mutation.

In their follow-up study, the Watson lab and their collaborators in the Department of Genetics (Cambridge) asked how these developmental defects were inherited if not through genetic mutations. Their research showed that the Mtrr mutation substantially changed the epigenome in the sperm. The epigenome is a layer of regulation on top of the genome that can turn genes on or off, and in the case of sperm, is important for fitting the DNA inside the sperm head. The epigenome involves chemicals, such as methyl groups, that bind to DNA at specific locations to control how genes are expressed. Incidentally, the amount of folic acid in a cell directly relates to how many methyl groups it has to regulate gene expression. Typically, the epigenome is nearly “wiped clean” after each generation in germ cells like sperm.

This study shows that that the Mtrr mutation leads to changes in methylation of sperm DNA, and in some cases these changes are found in known regions of the genome that are protected from the normal ‘generational wiping’. These regions are candidates for passing epigenetic information from one generation to the next. Even though DNA methylation patterns were re-set in these regions in embryos and placentas of the grandprogeny, the researchers found that the genes associated with the methylation changes were misexpressed. This gene misexpression was also associated with increased risk of detrimental effects on health. The researchers hypothesize that the grandprogeny ‘remembers’ the epigenetic changes caused by folic acid deficiency in their grandfather’s sperm, which impacts gene expression and disease risk.

One of these genes was Hira. Since HIRA protein is part of the cell machinery that regulates the epigenome in sperm and eggs, its misexpression represents a candidate biomarker of so-called epigenetic inheritance, and perhaps it is even a molecular mediator of this type of non-genetic inheritance.

Overall, this research solidifies, at least in mice, that the detrimental effects of folic acid deficiency on health can last for multiple generations and moves us closer to understanding the molecular mechanism behind this phenomenon.

Funding: This research was funded by the Lister Institute of Preventative Medicine, a Wellcome Trust 4-year DTP in Developmental Mechanisms, the Centre for Trophoblast Research, and the MRC.

Reference: Blake et al. (2021) Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker. Nature Communications doi: 10.1038/s41467-021-24036-5