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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 normal decidualization. (A). Representative images of the reproductive tracts of the female WT and Kdm3bKO (KO) mice. Arrows indicate the embryo implantation sites stained by Chicago Blue dye in the uteri on dpc 4.5. (B). Representative images of the reproductive tracts of WT and KO mice on dpc 7.5. Arrows indicate larger and smaller embryos in the uteri of WT and KO mice, respectively. (C). The H&E-stained images of cross sections prepared from pregnant uteri of WT and KO mice on dpc 7.5. The arrow indicates a normal embryo in WT uterus. The arrowhead indicates an implantation site in KO uterus where the embryo was absorbed. (D). Kdm3bKO mice exhibited a reduced decidual response. As sketched in the upper panel, ovariectomized WT mice (n=8) and KO mice (n=6) were treated with 17β-estradiol and progesterone. Decidulization was mechanically induced and measured as described in Materials and Methods. Representative images of uterine decidualization in WT and KO mice were shown. The ratios of the stimulated uterine horn (S) weights to un-stimulated uterine horn (US) weights were determined by weighing the wet uterine tissues. **, p < 0.001 by Student's t test. (E). Alkaline phosphotase activity detected by histochemistry (green color) in WT and KO uterine horns receiving decidual stimuli. The slides were counter-stained with Nuclear Fast Red.
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Figure 7: Kdm3b is required for normal decidualization. (A). Representative images of the reproductive tracts of the female WT and Kdm3bKO (KO) mice. Arrows indicate the embryo implantation sites stained by Chicago Blue dye in the uteri on dpc 4.5. (B). Representative images of the reproductive tracts of WT and KO mice on dpc 7.5. Arrows indicate larger and smaller embryos in the uteri of WT and KO mice, respectively. (C). The H&E-stained images of cross sections prepared from pregnant uteri of WT and KO mice on dpc 7.5. The arrow indicates a normal embryo in WT uterus. The arrowhead indicates an implantation site in KO uterus where the embryo was absorbed. (D). Kdm3bKO mice exhibited a reduced decidual response. As sketched in the upper panel, ovariectomized WT mice (n=8) and KO mice (n=6) were treated with 17β-estradiol and progesterone. Decidulization was mechanically induced and measured as described in Materials and Methods. Representative images of uterine decidualization in WT and KO mice were shown. The ratios of the stimulated uterine horn (S) weights to un-stimulated uterine horn (US) weights were determined by weighing the wet uterine tissues. **, p < 0.001 by Student's t test. (E). Alkaline phosphotase activity detected by histochemistry (green color) in WT and KO uterine horns receiving decidual stimuli. The slides were counter-stained with Nuclear Fast Red.

Mentions: In agreement with reduced ovulation and fertilization, the pregnant rate of Kdm3bKO mice was also lower than that of WT mice after successful coitus as examined on dpc 4.5 and dpc 7.5. For the same reason, pregnant Kdm3bKO mice also carried fewer embryos than pregnant WT mice did on dpc 4.5 and dpc 7.5 (Supplementary Material: Table S1). The embryonic implantation sites in Kdm3bKO uteri were fewer and smaller when compared with those in WT uteri (Fig. 7A and B, and Table S1). Most embryos in Kdm3bKO uteri were either small or were being absorbed (Fig. 7C and data not shown). The small implantation sites and the failure in maintaining embryo growth and survival at these pregnant stages suggest that the endometrial stroma of Kdm3bKO mice might have an abnormal decidualization.


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 normal decidualization. (A). Representative images of the reproductive tracts of the female WT and Kdm3bKO (KO) mice. Arrows indicate the embryo implantation sites stained by Chicago Blue dye in the uteri on dpc 4.5. (B). Representative images of the reproductive tracts of WT and KO mice on dpc 7.5. Arrows indicate larger and smaller embryos in the uteri of WT and KO mice, respectively. (C). The H&E-stained images of cross sections prepared from pregnant uteri of WT and KO mice on dpc 7.5. The arrow indicates a normal embryo in WT uterus. The arrowhead indicates an implantation site in KO uterus where the embryo was absorbed. (D). Kdm3bKO mice exhibited a reduced decidual response. As sketched in the upper panel, ovariectomized WT mice (n=8) and KO mice (n=6) were treated with 17β-estradiol and progesterone. Decidulization was mechanically induced and measured as described in Materials and Methods. Representative images of uterine decidualization in WT and KO mice were shown. The ratios of the stimulated uterine horn (S) weights to un-stimulated uterine horn (US) weights were determined by weighing the wet uterine tissues. **, p < 0.001 by Student's t test. (E). Alkaline phosphotase activity detected by histochemistry (green color) in WT and KO uterine horns receiving decidual stimuli. The slides were counter-stained with Nuclear Fast Red.
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Related In: Results  -  Collection

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Figure 7: Kdm3b is required for normal decidualization. (A). Representative images of the reproductive tracts of the female WT and Kdm3bKO (KO) mice. Arrows indicate the embryo implantation sites stained by Chicago Blue dye in the uteri on dpc 4.5. (B). Representative images of the reproductive tracts of WT and KO mice on dpc 7.5. Arrows indicate larger and smaller embryos in the uteri of WT and KO mice, respectively. (C). The H&E-stained images of cross sections prepared from pregnant uteri of WT and KO mice on dpc 7.5. The arrow indicates a normal embryo in WT uterus. The arrowhead indicates an implantation site in KO uterus where the embryo was absorbed. (D). Kdm3bKO mice exhibited a reduced decidual response. As sketched in the upper panel, ovariectomized WT mice (n=8) and KO mice (n=6) were treated with 17β-estradiol and progesterone. Decidulization was mechanically induced and measured as described in Materials and Methods. Representative images of uterine decidualization in WT and KO mice were shown. The ratios of the stimulated uterine horn (S) weights to un-stimulated uterine horn (US) weights were determined by weighing the wet uterine tissues. **, p < 0.001 by Student's t test. (E). Alkaline phosphotase activity detected by histochemistry (green color) in WT and KO uterine horns receiving decidual stimuli. The slides were counter-stained with Nuclear Fast Red.
Mentions: In agreement with reduced ovulation and fertilization, the pregnant rate of Kdm3bKO mice was also lower than that of WT mice after successful coitus as examined on dpc 4.5 and dpc 7.5. For the same reason, pregnant Kdm3bKO mice also carried fewer embryos than pregnant WT mice did on dpc 4.5 and dpc 7.5 (Supplementary Material: Table S1). The embryonic implantation sites in Kdm3bKO uteri were fewer and smaller when compared with those in WT uteri (Fig. 7A and B, and Table S1). Most embryos in Kdm3bKO uteri were either small or were being absorbed (Fig. 7C and data not shown). The small implantation sites and the failure in maintaining embryo growth and survival at these pregnant stages suggest that the endometrial stroma of Kdm3bKO mice might have an abnormal decidualization.

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