A study carried out in animals was able to demonstrate, for the first time, how the gene-environment interaction during the craniofacial development of the embryo can give rise to cleft lip and palate. Researchers from the University of São Paulo (USP), in collaboration with the University College London, from the United Kingdom, managed to prove in an animal model that cleft lip and palate, also known as cleft lip, occurs as a result of the association of two events: one genetic and another caused by inflammation during pregnancy, during the formation and development of the embryo. In Brazil, it is estimated that this malformation affects one child in every 650 births. This Saturday, June 24, the National Cleft Awareness Day is celebrated, a date set to inform about the problem and contribute to the reduction of prejudice. Researchers have been following families with cases of cleft lip for years and there was a suspicion that for the malformation to occur an environmental component would be necessary, in addition to the genetic one, explains CEGH-CEL researcher Maria Rita Passos-Bueno, who coordinated the research published in Nature Communications. “By doing the genetic sequencing of these people, we saw that, although many of them had the mutation in the CDH1 gene, a significant number did not have the malformation. A piece was missing that fully explained what led to the occurrence of cleft lip”. The CDH1 gene (which encodes the E-cadherin protein) is one of the examples in which a mutation in one of its alleles can lead to the occurrence of cleft lip and also to a type of gastric cancer. “Several studies suggest a multifactorial inheritance pattern, which depends on the interaction of environmental and genetic factors. In addition, we have knowledge of the interaction/exposure to bacteria/inflammation and a certain type of gastric cancer associated with a CDH1 variant. Therefore, we decided to invest in the search for environmental factors. We chose inflammation based on literature data already associated with fissures”. Mutation The mutation interferes with the migration process of neural crest cells, those that are present in the development of the embryo and that differentiate for the formation of bones, cartilage, connective tissue of the face, among other cell types. With impaired neural crest migration during embryonic development, the differentiation process is impaired, potentially causing cleft lip. However, as Passos-Bueno points out, this variant alone could not fully explain the hereditary issue of cleft lip. “When the two alleles of CDH1 are missing, the embryo dies. When one allele is normal and the other is mutable, it is compatible with life and in most cases there is no malformation”, explains Passos-Bueno. The researchers began to investigate some environmental factor that could contribute to the process. “Data from the population of people with cleft lip show that obesity, diabetes and other situations that are pro-inflammatory, such as maternal infection (episodes of fever during pregnancy) are risk factors for the child to be born with clefts. The results of the study showed that inflammatory molecules, called cytokines, induce a hypermethylation of the CDH1 gene”, says Passos-Bueno. In the case of cleft lip and palate, epigenetics occurred, that is, biochemical changes in cells caused by environmental stimuli (in this case, inflammation) that promote the activation or silencing of genes, without causing changes in the individual’s genome. Methylation is a biochemical modification that consists of the addition of a methyl group to the DNA molecule through the action of enzymes. It is a natural and necessary process for the functioning of the organism, by which the expression of genes is modulated. However, when deregulated, as in the case of CDH1 hypermethylation, it can cause cell dysfunction and contribute to the development of diseases and malformations. However, research cannot show which types of inflammation, associated with the mutation, can lead to the malformation. “We still don’t have a clear picture of what these inflammations are. But it is important to be clear that an environmental risk factor alone will not lead to a cleft lip”, clarifies the researcher. Experiment In the study, in addition to the in vitro tests performed on human cells, the researchers performed experiments on mice and frogs to prove that inflammation was causing hypermethylation in the CDH1 gene. Cells and embryos from mice and frogs were exposed to environmental factors, through particles of bacteria that produce inflammation. Then, females with normal copies of the gene were also exposed to inflammation. When females with a mutated copy of the gene were exposed to inflammation, the researchers observed that the offspring had defects in neural crest migration, which may explain the appearance of the fissure. The research intends, in the future, to identify which inflammations, combined with the CDH1 variant, can lead to malformation. “We intend to investigate this issue. The identification of factors that activate maternal inflammation will be important for the establishment of preventive measures for cleft lip and palate”, concluded Passos-Bueno. The study was carried out at the Human Genome and Stem Cell Studies Center (CEGH-CEL) – one of the Research, Innovation and Dissemination centers (CEPIDs) funded by the São Paulo Research Foundation (Fapesp) – and the article Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction was published in Nature Communications.
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