Epigenetic effects: From cancer to neurology

SACRAMENTO, Calif.—Being able to repurpose drugs forindications beyond their original uses is always a blessing, and occasionally asecond use might be vastly different. Such is the case for the cancerchemotherapy agent, Topotecan, a topoisomerase inhibitor generally used totreat metastatic cancers, including ovarian, cervical and small-cell lungcancers. Previous research has discovered that it can un-silence the Angelmangene, which is epigenetically silenced. A University of California, Davis (UC Davis) team has discovered whereand how in the genome Topotecan enables this effect.

Topotecan functions by stabilizing the formation of the RNAstrands that form RNA-DNA hybrids known as 'R-loops,' in the Ube3a region ofthe gene15q11-q13. Angelman syndrome is the result of the loss of a maternallyinherited Ube3a gene at the 15q11-q13 locus, which is expressed in brainneurons. This rare neurodevelopmental disorder affects roughly 1 in 25,000, or150,000 people globally, and involves severe intellectual disability, seizures,motor impairments and laughing and smiling. Losing the same chromosomal region inheritedfrom the male parent results in Prader-Willi syndrome, a neurodevelopmentalcondition that presents with obsessive-compulsive behavior and insatiableappetites that can lead to morbid obesity.

"Topotecan also has an effect everywhere in the genome. Oneof the things it does is prevent cells from dividing. That's why it's a cancerdrug. But that's also a problem if you want to treat children, because it killsdividing cells," said Weston Powell, lead study author and a third-year medicalstudent in the Physician Scientist Training Program in the UC Davis School ofMedicine, adding that more work is needed to determine if Topotecan can beadjusted to only treat a targeted region.

The researchers noted that additional research is alsorequired to figure out if Topotecan can be used to therapeutically treatAngelman syndrome.

"Epigenetics is the layers that are put on top of thegenetic code by the environment. In the case of the imprinted inheritance ofthese two diseases, it's simply the environment of whether the chromosomestravel through the egg or the sperm," said Janine LaSalle, senior author of thestudy and a professor of microbiology and immunology. "But environmentalinfluences, such as diet and exposure to pollutants, also affect the epigeneticlayers and are becoming increasingly important in more common disorders such asautism."

New therapeutic options for Prader-Willi syndrome andAngelman syndrome would be welcome, as LaSalle notes that there are limitedeffective options for these diseases, though treating Prader-Willi patientswith growth hormone has shown some benefit.

According to LaSalle, who is also a researcher affiliatedwith the UC Davis MIND Institute, rearrangements in 15q are increasing, inprimates as well as humans, and her laboratory recently discovered anassociation between polychlorinated biphenyl levels and 15q rearrangements inhuman postmortem brain.

This work with the 15q region has potential in otherconditions as well. LaSalle says that there is a form of autism that resultsfrom duplications of this chromosomal region that causes a form of autism thatcomprises one percent of autism cases.

"There could be forms of autism that could be treated byunderstanding how drugs interact with this locus," she says.

"I think we're just probing at the tip of the iceberg ofunderstanding epigenetics in neurodevelopmental disorders," says LaSalle. "Itcertainly is attractive for especially a lot of the complex disorders such asautism, schizophrenia and intellectual disability, where there's not just onegene involved—there's a lot of gene pathways—and epigenetics really are theinterface of the genes and the environment…so understanding epigeneticpathways, especially these because these are so geneticallyencoded…understanding the mechanisms that the imprinting uses will definitelyhelp understand how genes are epigenetically regulated outside of imprintedgenes and for other, more common disorders."