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Fragile X protein's new role gives treatment clues
Fragile X mental retardation protein — or FMRP — oversees genes which package DNA. This newly identified role for FMRP may ultimately reveal ways to treat the symptoms of this inherited disorder, which is marked by developmental delays, intellectual disability, and at times autism.
The report appears in the September 7, 2017 issue of the journal Cell.
Robert Darnell PhD, is an investigator with the Howard Hughes Medical Institute (HHMI) at the Rockefeller University, and leader of the study. He finds this discovery "an exciting step toward a different kind of treatment approach," but is cautions as the results are on mice, and not yet tested in humans. Earlier studies had found FMRP appeared to "manage" production of a slew of proteins located at nerve synapses. But though scientists tried manipulating synaptic proteins to ease abnormalities caused by an absense of FMRP, that approach "hasn't borne fruit yet," says Darnell.
Instead, he and his colleagues then focused on regulating the production of proteins which alter DNA packaging. His team's previous work hinted FMRP controls a group of proteins called epigenetic regulators which help wind strands of DNA into complex structures called chromatin. Looser packaging allows genes to become active and shape proteins, while tighter packaging keeps genes quiet — a very effective way to control gene behavior. No one knew yet the role FMRP played in this process.
Now, Darnell's team has found FMRP is the top supervisor of protein production. When FMRP is missing, chromatin packaging goes awry and genes activate when they shouldn't.
Brd4 is one of those proteins FMRP controls. When researchers engineered mice to extinguish the FMRP protein, Brd4 target genes became active. But scientists had previously engineered a drug to curb Brd4 using the JQ1 molecule to prevent Brd4 from binding to chromatin. When researchers treated mice with JQ1, many abnormal activity levels of Brd4 target genes returned to normal.
Improvements were reflected in mouse brains. Mouse nerve cells shed excess dendritic spines - the neural protrusions that receive signals from other nerve cells, after treatment with JQ1. Extra dendritic spines sprouting from nerve cells are a well-known characteristic of fragile X.
Some aspects of mouse behavior improved as well. In an assay of repetitive behaviors, researchers counted how many marbles mice buried in their bedding during a 15-minute period. Mice without FMRP buried marbles obsessively - twice as many as normal mice. However, a week of treatment with JQ1 reversed that unusual behavior.
Mice without FMRP exhibited abnormal social behaviors as well. Normal mice spend about an equal amount of time exploring another mouse in their cage as they do exploring a plastic toy put there. However, mice lacking FMRP spent more time sniffing the new mouse. After JQ1 treatment, they shifted their curiosity towards exploring the toy.
These results suggest that some aspects of Fragile X Syndrome might be improved by tweaking FMRP. This approach isn't limited to Fragile X Syndrome either, explains Darnell, as half of children with Fragile X Syndrome also share some features of autism. Researchers found many genes that behave differently in Fragile X Syndrome children also seem to be abnormal in autistic children too.
The link to autism suggests that a therapy that could reset gene behavior in fragile X syndrome might also ease other developmental disorders. "There is a remarkable connection between fragile X syndrome and autism," says Darnell. He and his colleagues intend to continue exploring how these various targets interact, in order to clarify how they might be corrected when they veer off course.
• FMRP regulates chromatin-associated proteins in addition to synaptic proteins
• Misregulation of chromatin contributes to Fragile X syndrome
• Inhibition of Brd4 can alleviate transcriptional dysfunction and phenotypes of FXS
Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism. FXS results from the loss of function of fragile X mental retardation protein (FMRP), which represses translation of target transcripts. Most of the well-characterized target transcripts of FMRP are synaptic proteins, yet targeting these proteins has not provided effective treatments. 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. 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.
Keywords: Brd4, FXS, FMRP, chromatin, histones
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Mouse brain with too much Brd4 protein (BRIGHT GREEN) resulting from suppression of FMRP.
Higher levels of Brd4 increases symptoms of fragile X syndrome. Scale bar is 10 micrometers.
Image Credit: Korb et al./ Cell 2017