Enhancer RNA Reaches Out to Help DNA Loosen Up

Enhancer RNAs boost the rate of gene expression from protein-coding genes. These noncoding RNAs bind with CBP, a transcription coactivator, to stimulate histone acetyltransferase (HAT) activity. [Laboratory of Shelley Berger, Ph.D./Perelman School of Medicine, University of Pennsylvania]

There are times when chromatin, the more or less tightly packed complex of DNA and histone protein, can be induced to let its freak flags fly. These freak flags are acetyl groups, and when they fly, they signal that gene-coding regions are primed to hang loose—and indulge in profuse expression.

This form of gene activation may depend on a mechanism involving not just flamboyant acetyl groups, but also unassuming enhancer RNAs (eRNAs), molecules that are transcribed from DNA but do not code for protein. eRNAs are content to stay in the background, where they subtly facilitate the protein-coding regions of the genome.

Although eRNAs are modest, they have been brought into the spotlight by scientists based at the University of Pennsylvania School of Medicine. According to these scientists, eRNA can bind to CREB-binding protein (CBP), a transcription co-activator, to stimulate acetylation and, ultimately, gene expression.

This finding helps explain how enhancers, noncoding regions of the genome, manage to heighten the expression of nearby genes. Enhancers are known to be transcribed into eRNA. And eRNA has been implicated in enhanced gene expression. But the means by which eRNA exerts its effects have been unclear.

“Why are the noncoding regions of DNA transcribed at all? Their function has been mysterious,” said Shelley Berger, Ph.D., a professor of cell and developmental biology and director of the Penn Epigenetics Institute in the Perelman School of Medicine at the University of Pennsylvania. To clarify matters, Dr. Berger has been working with Daniel Bose, Ph.D., a postdoctoral fellow in her lab, study the regulation of gene expression from enhancers.

“The cells in our bodies share the same genes and DNA sequences and differ only in how these genes are expressed,” commented Dr. Bose. “Enhancers and eRNAs are critical for this process. Our work shows an exciting new way that eRNAs produce these different patterns of gene expression. We asked if eRNAs work directly with CBP and found that they do.”

This work appeared January 12 in the journal Cell, in an article entitled, “RNA Binding to CBP Stimulates Histone Acetylation and Transcription.” The article demonstrates that CBP binds directly to RNAs in vivo and in vitro. The RNAs bound to CBP in vivo include a large number of eRNAs.

“Using steady-state histone acetyltransferase (HAT) assays, we show that an RNA binding region in the HAT domain of CBP—a regulatory motif unique to CBP/p300—allows RNA to stimulate CBP’s HAT activity,” wrote the article’s authors. “At enhancers where CBP interacts with eRNAs, stimulation manifests in RNA-dependent changes in the histone acetylation mediated by CBP, such as H3K27ac, and by corresponding changes in gene expression.”

The authors concluded that eRNAs, through their direct interactions with CBP, contribute to the unique chromatin structure at active enhancers, which, in turn, is required for regulation of target genes.

“There is increased interest in enhancers and eRNAs in the cancer biology world because defective enhancers can cause too much or too little of a protein to be made, or can cause the coding region to be turned off or on, or can make a protein at the wrong time,” Dr. Berger commented. Knowing more about how enhancers and eRNAs function will help oncologists, since recent DNA sequencing of tumors from humans show that numerous mutations associated with cancers and other diseases occur in enhancer regions of the genome—not in protein-coding regions.

“Fundamentally, this is important science because we show that eRNAs have a key role throughout the genome and body to guide protein production,” Dr. Berger pointed out. “We identified, across the genome, that eRNAs were the most common type of RNA that bound to CBP, and that by making this interaction, eRNAs play a crucial role in regulating CBP activity and gene expression.”