Autism Protein Epigenetically Misregulated Study Finds, Opening Door for New Treatments

Fragile X syndrome (FXS) is a genetic disorder resulting in mild to moderate intellectual disability and is a leading cause of autism. FXS is a direct result of the loss of function of the fragile X mental retardation protein (FMRP)—a transcriptional repressor. Moreover, FMRP acts as a genetic conductor, orchestrating a symphony of genes that help shape DNA's 3D structure. Many of the known target transcripts for FMRP are synaptic proteins, yet targeting these proteins has not yielded effective treatments. Now, investigators at The Rockefeller University have published data showing that FMRP oversees a set of genes that alter how DNA is packaged. Findings from the new study were published recently in Cell in an article entitled “Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition.”

This newly discovered role for FMRP is important and may ultimately reveal novel ways to counter fragile X. Senior study investigator Robert Darnell, M.D., Ph.D., a Howard Hughes Medical Institute (HHMI) investigator at The Rockefeller University, calls the findings “an exciting step toward a different kind of treatment approach,” but cautions that the results, from studies of mice, are preclinical.

Misregulation of chromatin contributes to fragile X syndrome. [Korb et al./Cell 2017]

While scientists have studied FMRP for decades, how its absence leads to FXS hasn't been completely clear. Previous studies have shown that FMRP manages the production of a slew of proteins found at nerve cell synapses. For years, scientists thought that manipulating these synaptic proteins might ease some of the abnormalities caused by FMRP's absence. It's a promising approach, Dr. Darnell noted, but it “hasn't borne fruit yet.”

In the current study, Dr. Darnell and his colleagues focused on a different role for FMRP—regulating the synthesis of proteins that alter DNA packaging. The researcher's previous work had hinted that FMRP controls a group of proteins called epigenetic regulators. These proteins help wind strands of DNA into complex structures called chromatin. Looser packaging allows genes to become more active, while tighter packaging keeps genes quiet. In this way, chromatin-shaping proteins can control gene behavior.  

“We examined a group of FMRP targets that encode transcriptional regulators, particularly chromatin-associated proteins. Loss of FMRP in mice results in widespread changes in chromatin regulation and aberrant gene expression,” the authors wrote. “To determine if targeting epigenetic factors could reverse phenotypes associated with the disorder, we focused on Brd4, a BET protein and chromatin reader targeted by FMRP. Inhibition of Brd4 function alleviated many of the phenotypes associated with FXS. We conclude that loss of FMRP results in significant epigenetic misregulation and that targeting transcription via epigenetic regulators like Brd4 may provide new treatments for FXS.”

The researchers found that that FMRP sits at the top of a protein manufacturing plant—supervising the production of proteins that control genes. FMRP is like a “CEO overseeing a vast team of VPs,” Dr. Darnell remarked. And when the CEO goes missing, the VPs go wild.

Nerve cells lacking fragile X mental retardation protein have too many dendritic spines, small signal-receiving spindles coming off the main tendril (top). But treatment with a drug called JQ1 reduces the number of spines (bottom). Scale bar, 10 µm. [Korb et al./Cell 2017]

One such VP is a protein called Brd4, which adjusts the activity of other genes. When researchers engineered mice to lack FMRP, Brd4 was free to monkey with genes' activity levels. Scientists already have a drug that can curb Brd4's actions—a small molecule called JQ1 that prevents Brd4 from binding to chromatin. When the researchers treated mice with JQ1, many of the abnormal activity levels of Brd4 target genes returned to normal.

The research team found that improvements were also seen in the brain. After treatment with JQ1, mouse nerve cells that lacked FMRP shed excess dendritic spines—neural structures that receive signals from other nerve cells. (Extra spines sprouting from nerve cells are a well-known characteristic of FXS.)

Some aspects of mouse behavior improved, too. In an assay to measure repetitive behavior, researchers counted how many marbles mice buried in their bedding during a 15-minute window. Mice without FMRP buried marbles obsessively—roughly twice as many marbles as normal mice. But a week of JQ1 treatment reversed this unusual behavior.

Mice without FMRP exhibit abnormal social behaviors, too. Normal mice spend roughly equal time exploring another mouse and a plastic toy placed in their cage; mice lacking FMRP spend more time sniffing around the other mouse. After JQ1 treatment, the FMRP mice shifted their curiosity back toward the toy.

The results suggest that some aspects of FXS might be improved by tweaking FMRP's chromatin-shaping targets. This approach isn't limited to FXS, either, Darnell says. He points out that half of the children with the syndrome also show some features of autism. Many of the genes that were behaving differently in those with fragile X also seem to be abnormal in cases of autism too, the researchers found.

The link to autism suggests that a therapy that resets gene behavior in FXS may also ease other developmental disorders. “There is a remarkable connection between FXS and autism,” Dr. Darnell concluded.