Could DNA hydroxymethylation be crucial in influencing steroid hormone signaling in endometrial biology and endometriosis?

Endometriosis affects 10% of reproductive-aged women. It is characterized by the growth of the endometrium, outside the uterus and is associated with infertility and chronic abdominal pain. Lack of noninvasive diagnostic tools and early screening tests results in delayed treatment and subsequently increased disease severity. Endometriosis is a disease associated with a deregulated hormonal response, therefore, understanding the molecular mechanisms that govern this hormonal interplay is of paramount importance. DNA methylation is an epigenetic mark that regulates gene expression and is often associated with genes that code for steroid receptors and enzymes associated with estrogen synthesis and metabolism in endometriosis. DNA hydroxymethylation, which is structurally similar to methylation but functionally different, is a biologically critical mechanism that is also known to regulate gene expression. Ten Eleven Translocation (TET) proteins mediate hydroxymethylation. However, the role of DNA hydroxymethylation or TETs in the endometrium remains relatively unexplored. Currently, the "gold standard" technique used to study methylation patterns is bisulfite genomic sequencing. This technique also detects hydroxymethylation but fails to distinguish between the two, thereby limiting our understanding of these two processes. The presence of TETs in the male and female reproductive tract and its contribution to endometrial cancer makes it an important factor to study in endometriosis. This review summarizes the role of DNA methylation in aberrant steroid hormone signaling and hypothesizes that hydroxymethylation could be a factor influencing hormonal instability seen in endometriosis.