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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 required for maintaining normal levels of 17β-estradiol. (A). The concentrations of 17β-estradiol in the serum samples prepared from WT and Kdm3bKO (KO) mice on day 8 of pregnancy (n=6), at 40 hours after PMSG injection (n=6), and at 24 hours after hCG injection (n=3). (B). The concentrations of progesterone in the serum samples of WT and KO mice on day 8 pregnancy (n=6) and at 24 hours after hCG injection (n=3). (C). The relative expression levels of Cyp19a1 mRNA in the ovaries of untreated WT and KO mice (n=5).
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Figure 8: Kdm3b is required for maintaining normal levels of 17β-estradiol. (A). The concentrations of 17β-estradiol in the serum samples prepared from WT and Kdm3bKO (KO) mice on day 8 of pregnancy (n=6), at 40 hours after PMSG injection (n=6), and at 24 hours after hCG injection (n=3). (B). The concentrations of progesterone in the serum samples of WT and KO mice on day 8 pregnancy (n=6) and at 24 hours after hCG injection (n=3). (C). The relative expression levels of Cyp19a1 mRNA in the ovaries of untreated WT and KO mice (n=5).

Mentions: The functions of the female reproductive organs are tightly regulated by ovarian steroid hormones including estradiol and progesterone. After dpc 4.5, a high level of progesterone and a low level of estradiol in mice work coordinately to maintain normal pregnancy 23. On dpc 7.5, the average concentration of 17β-estradiol in the sera of Kdm3bKO female mice was only 50% of that in the sera of WT female mice. In WT and Kdm3bKO female mice with estrous cycles synchronized by PMSG and hCG treatments, the levels of 17β-estrodiol were also significantly lower in the sera of Kdm3bKO mice versus WT mice at 40 hours post PMSG treatment and at 24 hours post hCG treatment (Fig. 8A). However, the progesterone concentration showed no significant difference between these two mouse groups (Fig. 8B). Since the majority of 17β-estradiol is synthesized by the aromatase (Cyp19a1) expressed in the ovarian granulosa cells where Kdm3b is highly expressed, we examined Cyp19a1 expression in the ovaries of Kdm3bKO mice. Real-time RT-PCR analysis revealed no difference in Cyp19a1 mRNA expression between Kdm3bKO and WT ovaries (Fig. 8C), suggesting that Kdm3b knockout-induced decrease in 17β-estradiol is not caused by any changes of Cyp19a1 expression.


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 required for maintaining normal levels of 17β-estradiol. (A). The concentrations of 17β-estradiol in the serum samples prepared from WT and Kdm3bKO (KO) mice on day 8 of pregnancy (n=6), at 40 hours after PMSG injection (n=6), and at 24 hours after hCG injection (n=3). (B). The concentrations of progesterone in the serum samples of WT and KO mice on day 8 pregnancy (n=6) and at 24 hours after hCG injection (n=3). (C). The relative expression levels of Cyp19a1 mRNA in the ovaries of untreated WT and KO mice (n=5).
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Related In: Results  -  Collection

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Figure 8: Kdm3b is required for maintaining normal levels of 17β-estradiol. (A). The concentrations of 17β-estradiol in the serum samples prepared from WT and Kdm3bKO (KO) mice on day 8 of pregnancy (n=6), at 40 hours after PMSG injection (n=6), and at 24 hours after hCG injection (n=3). (B). The concentrations of progesterone in the serum samples of WT and KO mice on day 8 pregnancy (n=6) and at 24 hours after hCG injection (n=3). (C). The relative expression levels of Cyp19a1 mRNA in the ovaries of untreated WT and KO mice (n=5).
Mentions: The functions of the female reproductive organs are tightly regulated by ovarian steroid hormones including estradiol and progesterone. After dpc 4.5, a high level of progesterone and a low level of estradiol in mice work coordinately to maintain normal pregnancy 23. On dpc 7.5, the average concentration of 17β-estradiol in the sera of Kdm3bKO female mice was only 50% of that in the sera of WT female mice. In WT and Kdm3bKO female mice with estrous cycles synchronized by PMSG and hCG treatments, the levels of 17β-estrodiol were also significantly lower in the sera of Kdm3bKO mice versus WT mice at 40 hours post PMSG treatment and at 24 hours post hCG treatment (Fig. 8A). However, the progesterone concentration showed no significant difference between these two mouse groups (Fig. 8B). Since the majority of 17β-estradiol is synthesized by the aromatase (Cyp19a1) expressed in the ovarian granulosa cells where Kdm3b is highly expressed, we examined Cyp19a1 expression in the ovaries of Kdm3bKO mice. Real-time RT-PCR analysis revealed no difference in Cyp19a1 mRNA expression between Kdm3bKO and WT ovaries (Fig. 8C), suggesting that Kdm3b knockout-induced decrease in 17β-estradiol is not caused by any changes of Cyp19a1 expression.

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