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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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Effects of Kdm3b knockout on ovulation and fertilization. (A). Representative images of oocytes ovulated by WT and Kdm3bKO (KO) mice on dpc 1.5. Note that the embryonic cells from WT mice show an oval shape and smooth edge, while the embryonic cells from KO mice show irregular shapes and rough edges. (B). The average numbers of total and fertilized oocytes collected from WT or KO female mice on dpc 1.5. (C). Representative images of oocytes ovulated by gonadotropin-treated WT and Kdm3bKO mice on dpc 1.5. The schedules for PMSG and hCG treatments of female mice are indicated. Fertile WT male mice were housed with treated females on day 3. Ovulation was examined in the morning (dpc 1.5) on day 5. (D). The average numbers of total and fertilized oocytes collected from gonadotropin-treated WT or KO female mice on dpc 1.5. Data in panels B and D are presented as mean ± standard deviation. *, p < 0.05 by Student's t test.
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Figure 6: Effects of Kdm3b knockout on ovulation and fertilization. (A). Representative images of oocytes ovulated by WT and Kdm3bKO (KO) mice on dpc 1.5. Note that the embryonic cells from WT mice show an oval shape and smooth edge, while the embryonic cells from KO mice show irregular shapes and rough edges. (B). The average numbers of total and fertilized oocytes collected from WT or KO female mice on dpc 1.5. (C). Representative images of oocytes ovulated by gonadotropin-treated WT and Kdm3bKO mice on dpc 1.5. The schedules for PMSG and hCG treatments of female mice are indicated. Fertile WT male mice were housed with treated females on day 3. Ovulation was examined in the morning (dpc 1.5) on day 5. (D). The average numbers of total and fertilized oocytes collected from gonadotropin-treated WT or KO female mice on dpc 1.5. Data in panels B and D are presented as mean ± standard deviation. *, p < 0.05 by Student's t test.

Mentions: Next, we compared the morphology and function of Kdm3bKO and WT ovaries. We observed that all stages of follicles were present and corpus luteums formed normally in Kdm3bKO ovaries (Supplementary Material: Fig. S2A). We further compared ovulation function and fertilization efficiency in Kdm3bKO and WT female mice at dpc 1.5. Five WT females discharged an average of 8.4 oocytes per mouse, while 4 of 5 examined Kdm3bKO females only discharged an average of 4.6 oocytes per mouse. Interestingly, about 81% (34 out of 42) of oocytes in WT females were fertilized, but only 43% (10 out of 23) of oocytes in Kdm3bKO females were fertilized (Fig. 6A and B). The fertilized oocytes harvested from Kdm3bKO mice also exhibited abnormal morphologies when compared with those from WT mice (Fig. 6A). Furthermore, although PMSG and hCG treatment-induced super ovulation was not significantly different between Kdm3bKO and WT mice, the fertilization rate in Kdm3bKO mice was only 8%, which was almost 7 fold lower than the 54% fertilization rate in WT mice (Fig. 6C and D). These results suggest that Kdm3b is required for producing normal number of oocytes with high quality and for maintaining an efficient fertilization rate.


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)

Effects of Kdm3b knockout on ovulation and fertilization. (A). Representative images of oocytes ovulated by WT and Kdm3bKO (KO) mice on dpc 1.5. Note that the embryonic cells from WT mice show an oval shape and smooth edge, while the embryonic cells from KO mice show irregular shapes and rough edges. (B). The average numbers of total and fertilized oocytes collected from WT or KO female mice on dpc 1.5. (C). Representative images of oocytes ovulated by gonadotropin-treated WT and Kdm3bKO mice on dpc 1.5. The schedules for PMSG and hCG treatments of female mice are indicated. Fertile WT male mice were housed with treated females on day 3. Ovulation was examined in the morning (dpc 1.5) on day 5. (D). The average numbers of total and fertilized oocytes collected from gonadotropin-treated WT or KO female mice on dpc 1.5. Data in panels B and D are presented as mean ± standard deviation. *, p < 0.05 by Student's t test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4400382&req=5

Figure 6: Effects of Kdm3b knockout on ovulation and fertilization. (A). Representative images of oocytes ovulated by WT and Kdm3bKO (KO) mice on dpc 1.5. Note that the embryonic cells from WT mice show an oval shape and smooth edge, while the embryonic cells from KO mice show irregular shapes and rough edges. (B). The average numbers of total and fertilized oocytes collected from WT or KO female mice on dpc 1.5. (C). Representative images of oocytes ovulated by gonadotropin-treated WT and Kdm3bKO mice on dpc 1.5. The schedules for PMSG and hCG treatments of female mice are indicated. Fertile WT male mice were housed with treated females on day 3. Ovulation was examined in the morning (dpc 1.5) on day 5. (D). The average numbers of total and fertilized oocytes collected from gonadotropin-treated WT or KO female mice on dpc 1.5. Data in panels B and D are presented as mean ± standard deviation. *, p < 0.05 by Student's t test.
Mentions: Next, we compared the morphology and function of Kdm3bKO and WT ovaries. We observed that all stages of follicles were present and corpus luteums formed normally in Kdm3bKO ovaries (Supplementary Material: Fig. S2A). We further compared ovulation function and fertilization efficiency in Kdm3bKO and WT female mice at dpc 1.5. Five WT females discharged an average of 8.4 oocytes per mouse, while 4 of 5 examined Kdm3bKO females only discharged an average of 4.6 oocytes per mouse. Interestingly, about 81% (34 out of 42) of oocytes in WT females were fertilized, but only 43% (10 out of 23) of oocytes in Kdm3bKO females were fertilized (Fig. 6A and B). The fertilized oocytes harvested from Kdm3bKO mice also exhibited abnormal morphologies when compared with those from WT mice (Fig. 6A). Furthermore, although PMSG and hCG treatment-induced super ovulation was not significantly different between Kdm3bKO and WT mice, the fertilization rate in Kdm3bKO mice was only 8%, which was almost 7 fold lower than the 54% fertilization rate in WT mice (Fig. 6C and D). These results suggest that Kdm3b is required for producing normal number of oocytes with high quality and for maintaining an efficient fertilization rate.

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