Famine, drug abuse and even stress can “silence” certain genes, causing health problems in generations to come. Now scientists are asking: could therapies that change parental gene expression benefit their children?
Researchers at The Scripps Research Institute (TSRI) report new evidence suggesting the answer may be yes. In a study using mouse models of Huntington’s disease, treatment of parent animals with a drug compound led to reduced symptoms and delayed disease onset in their offspring. The findings point to a potential route for altering disease risk across generations through targeted epigenetic therapies.
Study Overview and Key Findings
The research focused on Huntington’s disease, a hereditary neurodegenerative disorder that progressively impairs motor control and cognition. More than a quarter of a million Americans are estimated to either have Huntington’s disease or be at risk of inheriting it. Although genetic testing can identify those who carry the mutation, effective prevention or symptom-reducing treatments remain limited.
Scientists led by Elizabeth Thomas at TSRI examined whether a class of compounds called histone deacetylase (HDAC) inhibitors could produce beneficial epigenetic changes that extend to the next generation. Epigenetics describes modifications that influence gene expression without altering the underlying DNA sequence. One common mechanism is DNA methylation, which can silence genes and be influenced by environmental factors such as diet, toxins or stress. These epigenetic marks can sometimes be transmitted across generations, affecting offspring health.
Earlier work in the Thomas lab identified several HDAC inhibitors with therapeutic potential. The team selected one compound known as HDACi 4b, originally developed by TSRI Professor Joel Gottesfeld, for detailed study. Previous experiments showed HDACi 4b reduced symptoms and delayed disease onset in Huntington’s disease mouse models. The new study asked whether parental treatment with HDACi 4b could produce epigenetic changes that benefit offspring.
Initial experiments examined gene expression in brain and muscle tissue from treated mice and found alterations in genes related to DNA methylation pathways. Supplementary tests using human patient fibroblast cells showed that HDACi 4b produced changes in DNA methylation across the genome and, notably, affected a greater number of genes on the male-specific Y chromosome than on other chromosomes.
To test transgenerational effects, the team treated a group of male mice that carried a human Huntington’s disease mutation with HDACi 4b, while a comparable control group received no treatment. After one month of treatment, these males were bred and their offspring were evaluated for Huntington’s-related symptoms. Female offspring showed no measurable differences between groups, but male offspring born to the treated fathers exhibited a meaningful improvement: delayed disease onset and reduced motor and cognitive deficits. These improvements were evident in behavioral assessments of balance, speed and memory.
Implications and Next Steps
These results demonstrate for the first time that a drug treatment administered to parents can produce epigenetic alterations that benefit their offspring in a neurodegenerative disease model. The findings raise several important questions and open avenues for further research. Key topics for follow-up include whether similar beneficial effects can be transmitted through the female germline, whether the positive changes persist beyond a single generation (for example, in grandchildren or great-grandchildren), and how broadly these effects apply across different HDAC inhibitors and disease contexts.
The research team is particularly interested in how clinically used HDAC inhibitors—several of which are already approved to treat certain cancers or bipolar disorder—might affect the offspring of patients who receive them. Because many people treated with these drugs have children, understanding potential transgenerational impacts is clinically relevant and important for public health guidance.
Funding for the research came from the National Institutes of Health (U01NS063953). The study was reported in the Early Edition of the Proceedings of the National Academy of Sciences (PNAS) and led by Elizabeth A. Thomas with co-authors Haiqun Jia, Charles D. Morris, Roy M. Williams, and Jeanne F. Loring. The PNAS article is titled “HDAC inhibition imparts beneficial transgenerational effects in Huntington’s disease mice via altered DNA and histone methylation” (published online December 22, 2014, doi:10.1073/pnas.1421285111).
Contact: Madeline McCurry-Schmidt, Scripps Research Institute. Source: Scripps Research Institute press release. Image credit: Dr. Steven Finkbeiner, Gladstone Institute of Neurological Disease and the University of California San Francisco.