A chromatin-loosening drug already approved as a cancer therapeutic may have another application—reversing the social deficits associated with autism spectrum disorder (ASD). If chromatin is packed too tightly, it can entomb genes, preventing their expression by closing them off from the cell's transcriptional machinery.
Effectively disinterring genes, and thereby allowing them to be expressed again, is a strategy that has been pursued in the development of anticancer drugs such as romidepsin, which potently inhibits histone deacetylases (HDACs), histone modifiers that remodel chromatin and regulate the transcription of targeted genes.
It happens that the genes affected by romidepsin have roles in both cancer and autism, say scientists based at the University of Buffalo. According to these scientists, brief treatment with a very low dose of romidepsin restored social deficits in animal models of autism in a sustained fashion.
This effect lasted for three weeks, spanning the juvenile to late adolescent period, a critical developmental stage for social and communication skills. That is equivalent to several years in humans, suggesting the effects of a similar treatment could potentially be long-lasting.
Detailed results from this work appeared March 12 in the journal Nature Neuroscience, in an article entitled “Social Deficits in Shank3-Deficient Mouse Models of Autism Are Rescued by Histone Deacetylase (HDAC) Inhibition.” In this study's mouse model of autism, HDAC2 is abnormally high, which makes the chromatin in the nucleus very tight, preventing genetic material from accessing the transcriptional machinery it needs to be expressed.
“…brief treatment with romidepsin…alleviated social deficits in Shank3-deficient mice,” the article's authors indicated. “HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits.”
“The HDAC inhibitor loosens up the densely packed chromatin so that the transcriptional machinery gains access to the promoter area of the genes; thus they can be expressed,” explained Zhen Yan, Ph.D., a professor of physiology and biophysics at the State University of New York at Buffalo and the senior author of the Nature Neuroscience paper. “Once HDAC2 is upregulated, it diminishes genes that should not be suppressed, and leads to behavioral changes, such as the autism-like social deficits.”
Earlier work carried out by Dr. Yan and colleagues revealed how the loss of Shank 3 disrupts neuronal communications by affecting the function of the NMDA (n-methyl-D-aspartate) receptor, a critical player in regulating cognition and emotion, leading to deficits in social preference that are common in
“Autism involves the loss of so many genes,” Dr. Yan continued. “To rescue the social deficits, a compound has to affect a number of genes that are involved in neuronal communication.”
“The extensive overlap in risk genes for autism and cancer, many of which are chromatin remodeling factors, supports the idea of repurposing epigenetic drugs used in cancer treatment as targeted treatments for autism.”
“Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits,” the Nature Neuroscience article detailed. “At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice.”
The rescue effect on gene expression was widespread. When Dr. Yan and her co-authors conducted genome-wide screening, they found that romidepsin restored the majority of the more than 200 genes that were suppressed in the autism animal model they used.
“The advantage of being able to adjust a set of genes identified as key autism risk factors may explain the strong and long-lasting efficacy of this therapeutic agent for autism,” Dr. Yan suggested. In their paper, Dr. Yan and her co-authors offered the following conclusion: “Taken together, the findings from the current study highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for autism spectrum disorder patients bearing SHANK3 mutations.”