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The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function.

Liu Z, Chen X, Zhou S, Liao L, Jiang R, Xu J - Int. J. Biol. Sci. (2015)

Bottom Line: We found that Kdm3b ablation decreased IGFBP-3 expressed in the kidney by 53% and significantly reduced IGFBP-3 in the blood, which caused an accelerated degradation of IGF-1 and a 36% decrease in circulating IGF-1 concentration.We also found Kdm3b was highly expressed in the female reproductive organs including ovary, oviduct and uterus.Importantly, these female reproductive phenotypes were associated with significantly increased levels of H3K9me1/2/3 in the ovary and uterus.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. ; 3. Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, China.

ABSTRACT
Kdm3b is a Jumonji C domain-containing protein that demethylates mono- and di-methylated lysine 9 of histone H3 (H3K9me1 and H3K9me2). Although the enzyme activity of Kdm3b is well characterized in vitro, its genetic and physiological function remains unknown. Herein, we generated Kdm3b knockout (Kdm3bKO) mice and observed restricted postnatal growth and female infertility in these mice. We found that Kdm3b ablation decreased IGFBP-3 expressed in the kidney by 53% and significantly reduced IGFBP-3 in the blood, which caused an accelerated degradation of IGF-1 and a 36% decrease in circulating IGF-1 concentration. We also found Kdm3b was highly expressed in the female reproductive organs including ovary, oviduct and uterus. Knockout of Kdm3b in female mice caused irregular estrous cycles, decreased 45% of the ovulation capability and 47% of the fertilization rate, and reduced 44% of the uterine decidual response, which were accompanied with a more than 50% decrease in the circulating levels of the 17beta-estradiol. Importantly, these female reproductive phenotypes were associated with significantly increased levels of H3K9me1/2/3 in the ovary and uterus. These results demonstrate that Kdm3b-mediated H3K9 demethylation plays essential roles in maintenance of the circulating IGF-1, postnatal somatic growth, circulating 17beta-estradiol, and female reproductive function.

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Kdm3b is highly expressed in the female mouse reproductive tracts. (A).Western blot analysis of Kdm3b expression in the uteri and ovaries of WT and Kdm3bKO (KO) mice. (B). IHC analysis of Kdm3b protein in the ovary of WT mice. The ovarian section of Kdm3bKO mice served as a negative control of IHC. I, interstitial stroma; F, follicles; T, thecal cells; CL, corpus luteum. (C). IHC analysis of Kdm3b in the oviduct. The oviduct section of KO mice served as a negative control of IHC. E, epithelium; S, stroma; L, lumen. (D). IHC analysis of Kdm3b in the uteri of WT mice, and Kdm3bKO mice (negative control of IHC). M, myometrium; UG, uterine gland; US, uterine stroma; LE, luminal epithelium; UL, uterine lumen. In the images of all IHC analysis, the Kdm3b immunostaining signal is in brown, and the cell nuclei stained by hematoxylin are in blue.
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Figure 4: Kdm3b is highly expressed in the female mouse reproductive tracts. (A).Western blot analysis of Kdm3b expression in the uteri and ovaries of WT and Kdm3bKO (KO) mice. (B). IHC analysis of Kdm3b protein in the ovary of WT mice. The ovarian section of Kdm3bKO mice served as a negative control of IHC. I, interstitial stroma; F, follicles; T, thecal cells; CL, corpus luteum. (C). IHC analysis of Kdm3b in the oviduct. The oviduct section of KO mice served as a negative control of IHC. E, epithelium; S, stroma; L, lumen. (D). IHC analysis of Kdm3b in the uteri of WT mice, and Kdm3bKO mice (negative control of IHC). M, myometrium; UG, uterine gland; US, uterine stroma; LE, luminal epithelium; UL, uterine lumen. In the images of all IHC analysis, the Kdm3b immunostaining signal is in brown, and the cell nuclei stained by hematoxylin are in blue.

Mentions: As the first step to understand the physiological functions of Kdm3b in female reproductive organs, we examined its expression profiles in these organs. Western blot analysis detected high levels of the 200 kD Kdm3b in the ovary and uterus of WT mice (Fig. 4A). In the ovary, IHC identified high levels of Kdm3b in the nuclei of granulosa cells of the primary, preantral and antral follicles and in the nuclei of thecal cells of the preantral and antral follicles. A weaker immunoreactivity of Kdm3b was also detectable in the nuclei of corpus luteum and interstitial stroma cells (Fig. 4B and data not shown). In the oviduct, Kdm3b was mainly detected in the nuclei of epithelial cells (Fig. 4C). In the uterus, Kdm3b was mainly detected in the nuclei of endometrial luminal and glandular epithelial cells and myometrial smooth muscle cells. Slightly weaker signals of Kdm3b immunostaining were also detected in the nuclei of certain stromal cells (Fig. 4D). No Kdm3b was detected in the ovary, oviduct and uterus of Kdm3bKO mice as expected (Fig. 4B-D). These results indicate that Kdm3b is highly and extensively expressed in the ovary, oviduct and uterus and hence may play important roles in modifying the epigenetic histone codes in these organs.


The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function.

Liu Z, Chen X, Zhou S, Liao L, Jiang R, Xu J - Int. J. Biol. Sci. (2015)

Kdm3b is highly expressed in the female mouse reproductive tracts. (A).Western blot analysis of Kdm3b expression in the uteri and ovaries of WT and Kdm3bKO (KO) mice. (B). IHC analysis of Kdm3b protein in the ovary of WT mice. The ovarian section of Kdm3bKO mice served as a negative control of IHC. I, interstitial stroma; F, follicles; T, thecal cells; CL, corpus luteum. (C). IHC analysis of Kdm3b in the oviduct. The oviduct section of KO mice served as a negative control of IHC. E, epithelium; S, stroma; L, lumen. (D). IHC analysis of Kdm3b in the uteri of WT mice, and Kdm3bKO mice (negative control of IHC). M, myometrium; UG, uterine gland; US, uterine stroma; LE, luminal epithelium; UL, uterine lumen. In the images of all IHC analysis, the Kdm3b immunostaining signal is in brown, and the cell nuclei stained by hematoxylin are in blue.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4400382&req=5

Figure 4: Kdm3b is highly expressed in the female mouse reproductive tracts. (A).Western blot analysis of Kdm3b expression in the uteri and ovaries of WT and Kdm3bKO (KO) mice. (B). IHC analysis of Kdm3b protein in the ovary of WT mice. The ovarian section of Kdm3bKO mice served as a negative control of IHC. I, interstitial stroma; F, follicles; T, thecal cells; CL, corpus luteum. (C). IHC analysis of Kdm3b in the oviduct. The oviduct section of KO mice served as a negative control of IHC. E, epithelium; S, stroma; L, lumen. (D). IHC analysis of Kdm3b in the uteri of WT mice, and Kdm3bKO mice (negative control of IHC). M, myometrium; UG, uterine gland; US, uterine stroma; LE, luminal epithelium; UL, uterine lumen. In the images of all IHC analysis, the Kdm3b immunostaining signal is in brown, and the cell nuclei stained by hematoxylin are in blue.
Mentions: As the first step to understand the physiological functions of Kdm3b in female reproductive organs, we examined its expression profiles in these organs. Western blot analysis detected high levels of the 200 kD Kdm3b in the ovary and uterus of WT mice (Fig. 4A). In the ovary, IHC identified high levels of Kdm3b in the nuclei of granulosa cells of the primary, preantral and antral follicles and in the nuclei of thecal cells of the preantral and antral follicles. A weaker immunoreactivity of Kdm3b was also detectable in the nuclei of corpus luteum and interstitial stroma cells (Fig. 4B and data not shown). In the oviduct, Kdm3b was mainly detected in the nuclei of epithelial cells (Fig. 4C). In the uterus, Kdm3b was mainly detected in the nuclei of endometrial luminal and glandular epithelial cells and myometrial smooth muscle cells. Slightly weaker signals of Kdm3b immunostaining were also detected in the nuclei of certain stromal cells (Fig. 4D). No Kdm3b was detected in the ovary, oviduct and uterus of Kdm3bKO mice as expected (Fig. 4B-D). These results indicate that Kdm3b is highly and extensively expressed in the ovary, oviduct and uterus and hence may play important roles in modifying the epigenetic histone codes in these organs.

Bottom Line: We found that Kdm3b ablation decreased IGFBP-3 expressed in the kidney by 53% and significantly reduced IGFBP-3 in the blood, which caused an accelerated degradation of IGF-1 and a 36% decrease in circulating IGF-1 concentration.We also found Kdm3b was highly expressed in the female reproductive organs including ovary, oviduct and uterus.Importantly, these female reproductive phenotypes were associated with significantly increased levels of H3K9me1/2/3 in the ovary and uterus.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. ; 3. Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, China.

ABSTRACT
Kdm3b is a Jumonji C domain-containing protein that demethylates mono- and di-methylated lysine 9 of histone H3 (H3K9me1 and H3K9me2). Although the enzyme activity of Kdm3b is well characterized in vitro, its genetic and physiological function remains unknown. Herein, we generated Kdm3b knockout (Kdm3bKO) mice and observed restricted postnatal growth and female infertility in these mice. We found that Kdm3b ablation decreased IGFBP-3 expressed in the kidney by 53% and significantly reduced IGFBP-3 in the blood, which caused an accelerated degradation of IGF-1 and a 36% decrease in circulating IGF-1 concentration. We also found Kdm3b was highly expressed in the female reproductive organs including ovary, oviduct and uterus. Knockout of Kdm3b in female mice caused irregular estrous cycles, decreased 45% of the ovulation capability and 47% of the fertilization rate, and reduced 44% of the uterine decidual response, which were accompanied with a more than 50% decrease in the circulating levels of the 17beta-estradiol. Importantly, these female reproductive phenotypes were associated with significantly increased levels of H3K9me1/2/3 in the ovary and uterus. These results demonstrate that Kdm3b-mediated H3K9 demethylation plays essential roles in maintenance of the circulating IGF-1, postnatal somatic growth, circulating 17beta-estradiol, and female reproductive function.

Show MeSH
Related in: MedlinePlus