The activation or deactivation of genes can occur due to adverse experiences in life, and these configurations can be passed from parents to children

Understanding child development from conception, discovering the impact of infections and other injuries during pregnancy, and seeking to optimize the quality of child hospital care are some of the main lines of research in pediatrics at the D’Or Institute for Research and Education (IDOR). However, to understand that the field only investigates the health and well-being of babies and newborns is a misconception.

There is a new scientific scenario understanding that, at the time when our organism is developing – as in the embryonic, fetal, and postnatal periods –, the occurrence of certain adverse factors can increase our susceptibility to chronic diseases in adulthood, such as diabetes, obesity, cardiovascular problems, and even mental disorders. This strand of study is called DOHaD (developmental origins of health and disease), and one of the most investigated topics within the field is epigenetics, the science that researches how the environment in which we live interacts with our gene expression, that is, in the activation or silencing of certain genes.

“When we talk about genetic alteration, it necessarily implies a mutation, a change in the sequence of the bases that make up the DNA. Epigenetics is not that”, begins Dr. Arnaldo Prata, pediatrician, professor, researcher, and coordinator of pediatrics at IDOR. “If all the cells in our body have all genes, our complete DNA, how do they turn into specific cells, be it a cardiomyocyte in the heart, or a neuron? To do so, the countless genes that are uninteresting for the function of a specific cell are deactivated, and only the general genes of the cell and those related to that specificity work. This activation and deactivation is a process that does not cause DNA mutation, but is still capable of causing relevant impacts, which can even be transmitted from parents to children. This is epigenetics.”, he explains.

Epigenetics emerged as a concept in the 1940s, but because it is still an incipient theory, it has only in recent years gained greater interest from scientists. The process of DNA methylation, a chemical modification that occurs in gene promoter regions and plays a significant role in activating and silencing gene expression, is one of the main focuses of research in the area.

Quickly recapitulating the concepts of genetics, our DNA is composed of two paired strands, composed of four nitrogenous bases that are chained sequentially through specific connections between them: Adenine (A) binds to Thymine (T) and Guanine (G) binds to Cytosine (C). Methylation is a process that occurs in the Cytosine-Guanine sequence, through the addition of a methyl radical to Cytosine. This process is very common in the so-called promoter regions, areas capable of making the gene active or inactive for certain transcription factors. “In this promoter region, if a methyl radical connects to cytosine, it becomes methylated and this modification affects the functioning of transcription factors, and that cell will no longer produce a certain protein, for example. Several diseases and aspects of health itself are regulated by these epigenetic mechanisms. We are a great algorithm”, illustrates the researcher.

Epigenetic Inheritance

In addition to biochemistry, epigenetics’s main interest is understanding how this molecular alteration triggers important clinical manifestations, and how they can be transmitted between generations.

“Studies have shown that, even today, descendants of generations that suffered famine in the Second World War present methylation of genes associated with stress regulation. There is a genetic process, during the generation of a new person, of zeroing methylations, but some are not undone. It is a complementary mechanism of evolution. If you live in a war situation, you need to be stressed and extra cautious to survive, and so does your child. It is as if the organism understood that it needs to prepare the next generations for the adversities of that environment”, exemplifies Dr. Arnaldo Prata.

Stress is, in fact, one of the research topics of the group led by the pediatrician. The group evaluates adverse experiences in the perinatal period and childhood, their impact on child development, and their relation with disease risk in adulthood. The investigative focus is the methylation of the glucocorticoid receptor gene, NR3C1, one of the most studied in the understanding of chronic stress. In 2022, the team published an important systematic review on the so-called “methylation sites” of this gene, as until then, in scientific articles, there was no clear mapping on which of the Cytosine-Guanine intervals the methylation studies were being carried out. The review mapped searches performed on the 47 methylation sites, providing a useful map for other epigenetic scientists. The publication was on the cover of the scientific journal Epigenetics, one of the most relevant in the area.

Later this year, IDOR’s pediatric team published in Epigenomics, another important journal in the area, the results of the most extensive study carried out so far, aimed at evaluating the methylation pattern of the NR3C1 gene in premature newborns admitted to a Neonatal-ICU, an environment associated with stressful experiences early in these babies’ lives. They compared these findings with those of full-term normal newborns in the first three months of life. The results showed that prematurity alone, regardless of the ICU environment, is already capable of increasing the percentage of methylation of the NR3C1 gene.

In another research still in the data collection phase, Dr. Arnaldo Prata, together with IDOR’s Internal Medicine research team (Prof. Heitor Siffert de Souza), is evaluating the influence of adverse childhood experiences, NR3C1 gene methylation and chronic inflammatory bowel disease in adults.

From the Hospital to the Lab, and back

Prata’s team’s interest in understanding epigenetics began about 5 years ago, when they left the exclusivity of clinical and hospital focus to delve into basic research, carried out in the laboratory. However, if epigenetics is one of the most recent lines of

study at IDOR, the area of research in pediatrics, in turn, is one of the oldest at the institution.

In 2014, Dr. Arnaldo Prata – at the time leader of the pediatric teams in the assistance area of Rede D’Or and recently retired professor at the Federal University of Rio de Janeiro (UFRJ) – decided to put into practice the desire to contribute even more to his area of medical training, dedicating more time to research in pediatrics. “At that time, I talked to Fernanda and Gito [Fernanda Tovar-Moll and Jorge Moll Neto, founders of IDOR], because there was not yet a research department in pediatrics, and as the Rede D’Or has a wide in the area, we agreed that it made sense for us to create the nucleus. In the beginning, it was Dr. Maria Clara Magalhães and me, and a year later Professor Antônio Ledo joined us. And we are, to this day, the 3 full professors of pediatrics, and also professors of the academic Master’s and Doctorate programs at IDOR!”, recalls the researcher.

Research in pediatrics is supported by modern equipment, including the PyroMark Q48, capable of pyrosequencing DNA and analyzing the percentage of methylation in genes of interest. The team is made up of multidisciplinary professionals, involving pediatricians, biologists, and research nurses, in addition to master’s, doctoral, post-doctoral, and scientific initiation students.

Dr. Arnaldo Prata informs that, even with the new lines of research, his group has not lost any interest in the quality of pediatric healthcare, and continues to develop studies and tools in the sector. He only emphasizes that the inclusion of epigenetics in the group’s investigative list was a differential offered by IDOR’s infrastructure. “We were excited about IDOR’s translational ability to link clinical research with basic, laboratory research. Today, it makes us proud to see the pediatric signs indicating our drawers in the laboratory. We’ve conquered the bench!”, he celebrates, playfully.

Written by Maria Eduarda Ledo de Abreu.