Low HDAC3 Expression Leads to Endometriosis-Linked Infertility
From fostering the development of new life to literally pushing out a 6 to 10-pound baby, the uterus is a pretty phenomenal organ. Every month it thickens its endometrial cells, the cells that line the inner wall of the uterus, in preparation for implantation of an embryo. But, if implantation doesn’t occur, the uterus sheds the thickened endometrial cells, and the cycle continues.
In women with endometriosis, however, this cycle feels anything but normal. Affecting more than 10% of women of reproductive age, endometriosis occurs when the endometrial cells find their way outside of the uterus and begin to grow on the ovaries, fallopian tubes, or other tissues in the pelvic region . These growths, though non-cancerous, can cause a great deal of pain, especially during a woman’s period when the thickened endometrial cells outside of the uterus have nowhere to go . In addition to pain during sex and incredibly heavy periods, women with endometriosis can suffer from infertility .
What causes this endometriosis-associated infertility remains unclear, but some recent studies have asked how epigenetic changes in endometrial cells of women with endometriosis could be contributing to infertility . In fact, in a study published just last week in Science Translational Medicine, Kim et al found that the presence of the epigenetic regulator histone deacetylase 3 (HDAC3) is severely reduced in the endometrial cells of women with endometriosis compared to healthy women. They also show that the presence of HDAC3 in endometrial cells of mice seems to be critical for the implantation and support of an embryo, potentially linking endometriosis and infertility.
Kim et al first isolated endometrial tissue from 21 women with endometriosis and 21 healthy women. Using an antibody that binds to HDAC3, they found that women with endometriosis had significantly lower levels of HDAC3 than healthy women. To further understand the role of HDAC3 in endometriosis, the researchers assessed HDAC3 levels in mice and baboons and found that HDAC3 is progressively lost as endometriosis develops, indicating that HDAC3 seems to be associated with the development of endometriosis.
Because of this stark difference in HDAC3 expression in endometriosis patients compared to healthy women, Kim et al created a mouse model that had lost expression of HDAC3 in the endometrial cells and asked what role HDAC3 plays in the uterus and how its loss might affect fertility. Intriguingly, they found a severe defect in the ability of embryos to implant in the uterus of mice without HDAC3. Similarly, when they artificially stimulated implantation in the mice, the endometrial cells did not undergo their typical changes that would support growth of an embryo, called decidualization. Together, these results indicate that the infertility seen in mice without HDAC3 is a consequence of both the inability of embryos to implant and of defects in decidualization.
As a histone deacetylase, HDAC3 regulates gene expression. To identify which genes HDAC3 regulates in the uterus, Kim et al used chromatin immunoprecipitation sequencing (ChIP-seq) and DNA microarray analysis of uteri from mice lacking HDAC3 and healthy mice. They found that HDAC3 may be responsible for directly suppressing the transcription of two collagen genes, COL1A1 and COL1A2. To further investigate the role of HDAC3 in collagen regulation, the researchers used either a stain able to detect collagen (for mice samples) or a combination of the stain and an antibody that binds to collagen type 1 (for human samples). Combined, the results showed that endometrial cells from both women and mice with endometriosis expressed more collagen proteins than their healthy counterparts. This increase in collagen expression aligns with the observation of increased fibrous tissue surrounding endometrial cells in women with endometriosis .
Interestingly, the researchers also found that p300, one of the proteins belonging to the histone acetyl transferase complex, seems to be recruited to COL1A1 and COL1A2 when HDAC3 is lost, indicating that other regulatory components are also involved in activating the collagen genes upon loss of HDAC3. Kim et al found that if they knocked down expression of both HDAC3 and p300, the collagen genes were no longer activated and that the expression of decidualization marker genes was recovered. These results demonstrate that normal expression of decidualization genes seems to occur when collagen gene expression is decreased.
This study suggests that loss of HDAC3 in the endometrium of women with endometriosis may lead to infertility through the embryo’s inability to implant as well as improper decidualization of the endometrium. The researchers also elucidated possible molecular mechanisms that lead to abnormal decidualization through the improper activation of collagen genes. Overall, this study provides a deeper understanding of what goes wrong in the endometrial cells during endometriosis and thus allows for the development of new treatments for women with endometriosis-associated infertility.
Original paper: Kim TH, Yoo JY, Choi KC, Shin JH, Leach RE, Fazleabas AT, Young SL, Lessey BA, Yoon HG, Jeong JW (2019). Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci Transl Med, 11(474). pii: eaaf7533. doi: 10.1126/scitranslmed.aaf7533.
 Mayo Clinic (2018, July 24). Endometriosis. https://www.mayoclinic.org/diseases-conditions/endometriosis/symptoms-causes/syc-20354656
 Borghese B, Zondervan KT, Abrao MS, Chapron C, Vaiman D (2017). Recent insights on the genetics and epigenetics of endometriosis. Clin Genet, 91(2):254-264. doi: 10.1111/cge.12897.
 Matsuzaki S, Canis M, Darcha C, Dechelotte P, Pouly JL, Bruhat MA (1999). Fibrogenesis in peritoneal endometriosis. A semi-quantitative analysis of type-I collagen. Gynecol Obstet Invest, 47(3):197-9.