Genes are sequences within the genome that code for instructions for production of proteins. Other regions of the genome, called non-coding regions, were initially thought to be junk and useless. However, now it is becoming increasingly clear that the non-coding DNA can influence the expression of genes (coding regions). For example, the expression of a gene can be enhanced by a non-coding DNA sequence called the enhancer. Similarly, a silencer can suppress the expression of a gene. Therefore, enhancers and silencers are transcriptional regulatory elements (1). Modifying these elements affects the expression of a gene. Scientists have used this technique to study the functions of genes.
In a recently published study, scientists have used this technique again. They discovered that repressing the expression of the gene Sox9 – critical for male sex development in mice – reverses the sex of the mice from male to female (2). The study, published in Science, deepens understanding of the normal process of sex determination in mammals. The findings could also have important implications for patients with differences in sex development (DSDs), in which reproductive organs don’t develop as expected.
The Sox9 gene is crucial for male differentiation and the proper formation of testes; if Sox9 is mutated or incorrectly expressed, an individual who is chromosomally male (XY) can develop ovaries instead of testes. Previously, it was known that some patients with DSDs have changes in their genome near the Sox9 gene that alter its expression and lead to sex reversal. But it was unclear exactly why.
In the current study, the scientists identified an enhancer (a short region of DNA that can increase gene transcription) that is necessary to regulate expression of the Sox9 gene. When the scientists deleted the enhancer in mouse models, they discovered that Sox9 expression was decreased enough to cause complete sex reversal; mouse embryos that were chromosomally male (XY) developed as phenotypically normal females, with ovaries that were indistinguishable from those of XX females. This is probably the first time scientists have identified an enhancer of Sox9 that, when deleted, causes sex reversal in mice. It could also be the case in other mammals.
The findings could help improve the genetic diagnosis of patients with DSDs in the future; currently, only about 20 percent of such patients receive a genetic diagnosis. Often genes important for sex determination are also crucial for other developmental processes, and a mutation in one gene or its regulatory region can impact a patient’s health in many ways. As we begin to understand the genetic underpinnings of these disorders, we can improve our care of these patients.
For the future, the scientists are investigating other enhancers involved in the regulation of Sox9 and other sex-determining genes, and hope to also understand how Sox9 expression is repressed in females, leading to the development of ovaries.