Anti-convulsant drug can modify DNA conformation and interact with chromosome proteins

September 28, 2020

Results of recent studies involving valproic acid, used for decades as an anti-convulsant drug, show that it can interact with the conformation of DNA and regulate gene expression.

These are some of the key findings from a project led by biologist Maria Luiza S. Mello at the University of Campinas (UNICAMP) in the state São Paulo, Brazil, with the collaboration of Benedicto de Campos Vidal, Emeritus Professor in the Biology Institute’s Department of Structural and Functional Biology.

The group has been studying the functions of valproic acid, or sodium valproate (VPA), for over a decade and have demonstrated the compound’s action on the expression of genes associated with diabetes in cellular models (read more at: agencia.fapesp.br/23819).

Its interaction with DNA is reported in an article published in the International Journal of Biological Macromolecules. The study was part of a Thematic Project supported by FAPESP to study the action of VPA. “Elucidating the drug’s action mechanisms is important because it paves the way for novel pharmaceutical research,” Mello said.

Changes in histones and DNA

The epigenetic action of VPA – its capacity to influence gene expression without changing the subject’s DNA – was already well-known. “In 2017, Iranian researchers mooted the possibility of an action mechanism that was not only epigenetic but also involved direct interaction with the structure of histone H1,” Mello said. “So we decided to study how histones and DNA itself respond to VPA.” Histones are cell nucleus proteins and key components of chromatin, the substance of chromosomes. These are made up of DNA tightly wound around histones.

The group tested samples containing VPA-DNA and VPA-histone mixtures. They analyzed the interactions between H1, H3, and VPA by means of high-performance polarization microscopy and Fourier-transform infrared microspectroscopy, using equipment previously acquired by FAPESP for Campos Vidal.

“The samples with DNA, histones, and VPA were analyzed first under the polarization microscope and then under the infrared microspectroscope” Mello said. This type of measurement, performed with a spectroscope coupled to a special microscope, produces a spectral signature of molecular structure – a graphical record of how the molecules are organized.

The graph of the signature displays curves with peaks and troughs. “The frequency of the peaks points to a specific chemical group,” Mello said.

The group then compared histone and DNA organization with and without VPA. “We found that VPA can cause changes in the conformation, or spatial arrangement, of the two histones of interest, H1 and H3. In addition, we observed changes in DNA superstructure and molecular order,” he said. The next step will be to confirm whether the effect also occurs in cells treated with VPA in vitro.

Tumor gene expression

Besides this discovery, as part of the master’s research of Marina Amorim Rocha, in December 2019 the group published in Scientific Reports another important finding about the epigenetic action of VPA in laboratory-grown HeLa cells, which are derived from human cervical cancer cells. The focus for the investigation was a specific kind of epigenetic alteration known as DNA methylation.

Methylation occurs when a methyl group (CH3) is added to the carbon 5 position in the DNA nitrogenous base cytosine. “When this happens in the promoter of a gene, the functioning of the gene itself is altered,” Mello explained. If large-scale methylation occurs in the promoter of a tumor suppressor gene, for example, the gene can become inactive and cease performing its function.

The process can be manipulated, passively by inhibiting an enzyme involved in methylation or actively via a recently discovered pathway. “In this case a group of enzymes from the TET family lets these methylated cytosines transform themselves into other derived molecules until demethylation is complete,” Mello said.

In their study, the UNICAMP researchers found that the mechanism induced by VPA in HeLa cells was predominantly but not exclusively active. “It also acts via the passive pathway, and this finding can enhance the expertise of scientists dedicated to drug development,” Mello said. In other words, the fact that the compound reduces methylation in cultured cells during the stationary phase of the life cycle suggests that in future it can be tested as a candidate to reverse this process in cells that have stopped dividing.
-end-
About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at http://www.fapesp.br/en and visit FAPESP news agency at http://www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.

Fundação de Amparo à Pesquisa do Estado de São Paulo

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.