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. 2018 Jun;35(6):993-1003.
doi: 10.1007/s10815-018-1151-3. Epub 2018 Mar 14.

Histone demethylase KDM4A and KDM4B expression in granulosa cells from women undergoing in vitro fertilization

Adam J Krieg  1   2   3   4   5 , Sarah R Mullinax  6 , Frances Grimstad  2 , Kaitlin Marquis  2 , Elizabeth Constance  2 , Yan Hong  2 , Sacha A Krieg  1   7   2   5 , Katherine F Roby  8   9   10
Affiliations

Histone demethylase KDM4A and KDM4B expression in granulosa cells from women undergoing in vitro fertilization

Adam J Krieg et al. J Assist Reprod Genet. 2018 Jun.

Abstract

Purpose: To assess expression of the histone demethylases KDM4A and KDM4B in granulosa collected from women undergoing oocyte retrieval and to determine if expression was related to pregnancy outcome.

Methods: Cumulus and mural granulosa cells were obtained from women undergoing oocyte retrieval. KDM4A and KDM4B mRNA expression was determined by qRT-PCR. KDM4A and KDM4B proteins were immunohistochemically localized in ovarian tissue sections obtained from archival specimens.

Results: KDM4A and KDM4B protein was localized to oocytes, granulosa cells, and theca and luteal cells in ovaries from reproductive-aged women. KDM4A and KDM4B mRNA expression was overall higher in cumulus compared to mural granulosa. When comparing granulosa demethylase gene expression, KDM4A and KDM4B mRNA expression was higher in both cumulus and mural granulosa from not pregnant patients compared to patients in the pregnant-live birth group.

Conclusions: Histone demethylases KDM4A and KDM4B mRNA are differentially expressed in cumulus and mural granulosa. Expression of both KDM4A and KDM4B mRNA was lower in cumulus granulosa and mural granulosa from pregnant compared to not pregnant patients. These findings suggest that altered expression of histone demethylases may impact epigenetic changes in granulosa cells associated with pregnancy.

Keywords: Granulosa; Histone demethylase; IVF; KDM4; Ovary; Pregnancy.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Immunolocalization of KDM4A and KDM4B in human ovaries. KDM4B was immunolocalized to granulosa cells and theca in large and small follicles, corpora lutea, and granulosa and oocyte in primordial and primary follicles. In all cells, localization of KDM4B was confined to the nucleus. KDM4A immunostaining was localized to granulosa and luteal cells and was weakly and diffusely noted throughout the ovary. Due to the weaker level of staining, ×2 magnified images are presented for KDM4A. Control immunostaining using IgG-stained sections are presented. The figure includes results from four different ovaries and is representative of eight ovaries analyzed. Black arrowheads denote staining for KDM4B and KDM4A. Bar indicates 50 μm
Fig. 2
Fig. 2
Expression of KDM4A and KDM4B mRNA in cumulus and mural granulosa. Granulosa cells were collected at the time of oocyte retrieval; RNA was isolated and expression of KDM4A and KDM4B was assessed by qRT-PCR. Normalized data (∆CT) is expressed as fold change from the mean of the pregnant cohort. The median line ± 95% confidence intervals are shown. Pregnant-live birth (n = 31) versus not pregnant (n = 53) were compared by Mann-Whitney. *p < 0.04 pregnant-live birth versus not pregnant
Fig. 3
Fig. 3
Correlation of KDM4A and KDM4B mRNA expression in cumulus and mural granulosa cells. The correlation of the fold change values for expression of KDM4A and KDM4B mRNA in the cumulus granulosa (a) and mural granulosa (b) was determined for patients in the not pregnant (red) and pregnant-live birth (green) groups. Spearman’s rs values are indicated for each correlation. Spearman’s correlation (rs) = 1.0–0.8 very strong, 0.79–0.6 strong, 0.59–0.4 moderate
Fig. 4
Fig. 4
Correlation of KDM4 mRNA expression in cumulus and mural granulosa cells with patient age. The fold change values for expression of KDM4A and KDM4B mRNA in the cumulus and mural granulosa in pregnant-live birth (green) and not pregnant (red) groups did not correlate with patient age. Spearman’s correlation values are indicated (rs) = 1.0–0.8 very strong, 0.79–0.6 strong, 0.59–0.4 moderate, 0.39–0.2 weak, 0.19–0 very weak correlation
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