BRD4 Protein May be Therapeutic Target for Rett Syndrome, Study Suggests


By targeting a protein called BRD4, an experimental cancer treatment known as JQ1 reversed cellular abnormalities and extended survival in a mouse model of Rett syndrome, a study shows.

Results point toward BRD4 as a new potential target for Rett syndrome, scientists said.

The study, “Dysregulation of BRD4 Function Underlies Functional Abnormalities of MeCP2 Mutant Neurons,” was published in the journal Molecular Cell.


Mutations in the MECP2 gene, located in the X chromosome, cause nearly all cases of Rett syndrome. This gene codes for the MeCP2 protein, which regulates the activity of other genes and is especially important in brain development and function.


A team at Yale University wanted to know how mutations in MECP2 cause severe disruptions to nerve cell function that are observed in the cortex of Rett syndrome patients.

The scientists conducted studies in cell cultures and then applied their findings to a mouse model of Rett.

First, the team engineered human embryonic stem cells to express a mutation in the MECP2 gene known as R133C. This mutation, one of the most commonly observed in Rett syndrome, impairs the MeCP2 protein’s ability to bind to DNA. By selectively binding to specific spots in DNA, MeCP2 can effectively turn other genes “on” or “off,” which is critical to proper cellular development and function.

The stem cells were differentiated into a class of neurons called interneurons, which pass signals between motor and sensory nerve cells, and whose malfunction is key in Rett syndrome.

The mutation-bearing interneurons showed signs of incomplete maturation, such as small size, fewer connections with other neurons, and reduced electrical activity. They also showed impaired calcium surges. Neurotransmitter release — how one nerve cell communicates with another — depends heavily on calcium.

A subsequent small molecule screen revealed that an experimental cancer treatment called JQ1 shifted the mutated interneuron gene activity to more closely resemble that of healthy interneurons. JQ1 targets a protein called BRD4, which regulates gene activity by binding to specific sites on chromosomes.

The rescued gene activity included many genes that are quickly and temporarily activated in response to nerve signals, the so-called immediate early genes, or IEGs. In interneurons with the R133C mutation, JQ1 appeared to block the transcription of many of these IEGs, meaning their conversion to RNA.

Both MeCP2 and BRD4 appeared to bind to many of the same targets, implying that they work together to regulate these genes’ activity. The Yale team suggested that the loss of MeCP2 leads to greater gene expression and to binding of BRD4 to chromatin — found in chromosomes, and containing DNA and proteins — thereby contributing to a hyperactive state of interneurons.

In addition to rescued IEG activity, JQ1 restored calcium surges to patterns comparable to healthy nerve cells.

Building up the complexity of their model, the researchers grew the mutated interneurons into 3D cell models called organoids. Again, JQ1 reversed the abnormal gene regulation and signalling seen in mutant cells.

Experiments to test the effect of the R133C mutation in other neural cell types, such as glial cells, showed similar patterns of genetic dysregulation and impaired cellular development, which were also rescued by JQ1 treatment.

To find out whether these results extended beyond cell cultures, the team tested JQ1 in a mouse model of Rett syndrome.

Daily low doses of JQ1, beginning two weeks after birth, resulted in an 81% longer lifespan. Also, JQ1 significantly eased characteristic Rett manifestations, delaying the onset of hind limb clasping which resembles the hand stereotypies — or purposeless, repeated movements — seen in people with Rett.

“These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology [Rett development] and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT,” the scientists wrote.

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