1.The role of histone deacetylases 1/2 in regulating murine oogenesis.
Acta Physiologica Sinica 2021;73(3):527-534
Oogenesis is the basic reproductive process of female mammals and is essential for fertilization and embryo development. Recent studies have shown that epigenetic modifications play an important role in the regulation of mammalian reproductive processes (such as oogenesis, spermatogenesis, preimplantation embryo development and sex differentiation). Taking histone acetylation as an instance, the dynamic changes of histone acetyltransferases (HATs) and deacetylases (HDACs) are involved in the regulation of gene activation and inactivation when numerous key physiological events occur during reproduction. Thereinto, HDAC1 and HDAC2, which are highly homologous in terms of both structure and function, play a pivotal role in murine oogenesis. HDAC1 and 2 jointly regulate the global transcription and the incidence of apoptosis of growing oocytes and affect its subsequent growth and development, which reflects their compensatory function. In addition, HDAC1 and 2 also play a specific part in oogenesis respectively. It has shown that HDAC2 is more critical than HDAC1 for oocyte development, which regulates de novo DNA methylation and chromosome segregation. Reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development. Deficiency of HDAC1 causes the decreased proliferation of embryonic stem cells and the smaller embryoid bodies with irregular shape. In this review, we summarized the role and the current research progress of HDAC1/2 in murine oogenesis, to provide a reference for further understanding the relationship between epigenetic modifications and reproductive regulation.
Acetylation
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Animals
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Embryonic Development
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Female
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Histone Deacetylase 1/metabolism*
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Histone Deacetylase 2/metabolism*
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Histone Deacetylases/metabolism*
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Male
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Mice
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Oocytes
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Oogenesis
2.Role and mechanism of histone deacetylases in mouse neuronal development.
Yu-Wei BAI ; Meng-Long GUAN ; Tao ZHENG ; Shi-Ping LI ; Yi QU ; De-Zhi MU
Chinese Journal of Contemporary Pediatrics 2021;23(3):294-299
OBJECTIVE:
To study the role and mechanism of histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2) in mouse neuronal development.
METHODS:
The mice with Synapsin1-Cre recombinase were bred with
RESULTS:
The mice with
CONCLUSIONS
Deletion of
Animals
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Blotting, Western
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Histone Deacetylase 1/genetics*
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Histone Deacetylase 2
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Histone Deacetylases/genetics*
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Immunohistochemistry
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Mice
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Neurons/metabolism*
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Signal Transduction
3.Effect of Histone Deacetylase Inhibition on the Expression of Multidrug Resistance-associated Protein 2 in a Human Placental Trophoblast Cell Line.
Hong-Yu DUAN ; Dan MA ; Kai-Yu ZHOU ; ; Tao WANG ; Yi ZHANG ; ; Yi-Fei LI ; Jin-Lin WU ; Yi-Min HUA ; ; Chuan WANG ;
Chinese Medical Journal 2017;130(11):1352-1360
BACKGROUNDPlacental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process.
METHODSThe human choriocarcinoma-derived trophoblast cell line (Bewo cells) was treated with the HDAC inhibitors-trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA (siRNA) specific for HDAC1/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC1/2/3/ABCC2 messenger RNA (mRNA) and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively.
RESULTSTSA could inhibit total HDAC activity and HDAC1/2/3 expression in company with increase of MRP2 expression in Bewo cells. Reduction of HDAC1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L (vs. vehicle group, all P < 0.001), accompanied with dose-dependent induction of MRP2 expression (P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P < 0.001 for 5.0 μmol/L), whereas no significant differences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells were week, and no significant differences were noticed among these three groups (all P > 0.05). However, MRP2 expression was remarkably elevated in HDAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells (P < 0.001).
CONCLUSIONSHDACs inhibition could up-regulate placental MRP2 expression in vitro, and HDAC1 was probably to be involved in this process.
Cell Line ; Histone Deacetylase 1 ; metabolism ; Histone Deacetylase 2 ; metabolism ; Histone Deacetylase Inhibitors ; pharmacology ; Histone Deacetylases ; metabolism ; Humans ; Hydroxamic Acids ; pharmacology ; Microscopy, Fluorescence ; Multidrug Resistance-Associated Proteins ; genetics ; metabolism ; RNA, Messenger ; Trophoblasts ; cytology ; metabolism
4.Effects of trichostatin A on the interaction between HBx and histone deacetylase protein 1.
Ju-qiang HAN ; Qi-nong YE ; Li-Hua DING ; Jie-zhi LI ; Xiao YANG ; Cui-fen HUANG
Chinese Journal of Hepatology 2008;16(9):657-659
OBJECTIVESTo study the effects of trichostatin A (TSA) on protein-protein interaction between HBx and histone deacetylase protein 1 (HDAC1).
METHODSBoth HBx and HDAC1 expressing vectors were constructed by the method of routine molecular cloning. The expression of HBx and HDAC1 were observed by Western blot assay. The protein-protein interaction was tested between HBx and HDAC1 by GST pull-down in vitro as well as co-immunoprecipitation in vivo.
RESULTSBoth HBx and HDAC1 expressing vectors were successfully constructed. Protein-protein interaction between HBx and HDAC1 existed both in vitro and in vivo. TSA, an inhibitor of HDAC1, had no effect on the interaction between HBx and HDAC1.
CONCLUSIONSHBx interacts with HDAC1 in vivo and in vitro in a non- TSA dependent way.
Histone Deacetylase 1 ; metabolism ; Humans ; Hydroxamic Acids ; metabolism ; Immunoprecipitation ; Plasmids ; Protein Interaction Mapping ; Trans-Activators ; metabolism
5.Expressions of HDAC1 and HDAC2 in prostate cancer and their clinical implications.
National Journal of Andrology 2013;19(8):699-703
OBJECTIVETo detect the expressions of HDAC1 and HDAC2 proteins in prostate cancer and to explore their clinical significance.
METHODSWe detected the expressions of HDAC1 and HDAC2 proteins in the tissue samples of prostate cancer from 82 patients with complete clinical data by immunohistochemistry, and analyzed the correlation of the expressions of HDAC1 and HDAC2 with other clinicopathological parameters, such as Gleason scores, preoperative PSA levels, and postoperative survival time.
RESULTSHDAC1 and HDAC2 were expressed in 59.7 and 70.7% of the patients, respectively, located in the nuclei of cancer cells, more highly in those with higher than in those with lower Gleason scores (P < 0.05). No statistically significant differences were found in the expressions of HDAC1 and HDAC2 among those with different preoperative PSA levels and those of different ages (P > 0.05). Univariate analysis demonstrated that the HDAC2 expression, pre-operative PSA levels, Gleason scores and clinical stages of prostate cancer were important factors affecting the patients'survival (P < 0.05). Cox analysis indicated that the expression of HDAC2 was an independent index for the prognosis of prostate cancer (P = 0.017, HR = 2.265, 95% CI: 1.145 - 4.775).
CONCLUSIONThe increased expression of HDAC2 in prostate cancer can serve as an independent prognostic indicator, which has provided a theoretical base for the clinical application of HDACs in the diagnosis and prognosis of prostate cancer.
Aged ; Aged, 80 and over ; Histone Deacetylase 1 ; metabolism ; Histone Deacetylase 2 ; metabolism ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Prognosis ; Prostatic Neoplasms ; metabolism ; pathology
6.Efflect of miR-34a-Tangeted Regulation of HDACI on Apoptosis of AML Cells.
Chao WEN ; Yuan-Kang XIE ; Yi-Jian CHEN
Journal of Experimental Hematology 2019;27(3):790-795
OBJECTIVE:
To investigate the regulation of miR-34a on HDAC1 expression and its effect on the apoptosis of acute myeloid leukemia (AML) cells.
METHODS:
miR-34a mimics, miR-34a inhibitor and miR-34a scramble were transfected into HL-60 cells. The effects of miR-34a expression levels on proliferation and apoptosis of HL-60 cell were detected by CCK8 assay and flow cytometry respectively. The expression of HDAC1 protein was assessed by Western blot after regulating miR-34a expression, the 3'UTR of HDAC1 was cloned and ligated to construct a dual luciferase reporter vector, and then the dual luciferase reporter assay was applied to verify the target of miR-34a, the expression vector pcDNA3.1-HDAC1 was constructed, the interaction of miR-34a and HDAC1 was analyzed by reversion test.
RESULTS:
miR-34a over-expression could inhibit the proliferation of HL-60 cells and induce their apoptosis. Bioinformatics analysis indicated that the HDAC1 was a target gene of miR-34a. Western blot indicated that miR-34a overexpression down-regulated the expression of HDAC1. Dual luciferase reporter assay and reversion test showed that miR-34a could act at the 3-UTR of HDAC1 gene to regulate its expression.
CONCLUSION
miR-34a promotes the apoptosis of HL-60 cells via regulating HDAC1 expression.
Apoptosis
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Cell Proliferation
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HL-60 Cells
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Histone Deacetylase 1
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metabolism
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Humans
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Leukemia, Myeloid, Acute
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genetics
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MicroRNAs
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genetics
7.Inhibitory effect of VPA on multiple myeloma U266 cell proliferation and regulation of histone acetylation.
Yi-Fang ZHU ; Bao-Guo YE ; Jian-Zhen SHEN ; Cong-Meng LIN ; Fu-An LIN ; Song-Fei SHEN ; Cheng-Bo XU
Journal of Experimental Hematology 2010;18(3):638-641
This study was aimed to investigate the effects of sodium valproate (VPA) on the proliferation and regulation of histone acetylation of multiple myeloma cell line U266. U266 cells were treated with VPA. Cell proliferation was determined by CCK-8 assay, and cell cycle were analyzed by flow cytometry (FCM). The expression level of HDAC1 mRNA was detected by RT-PCR, and the protein levels of HDAC1 and histone H3, H4 acetylation was detected by Western blot. The results showed that the VPA inhibited the proliferation of U266 cells in concentration-and time-dependent manners.After exposure to different concentrations of VPA for 48 hours, the proportion of G(0)/G(1) cells increased, while the proportion of S phase cells decreased. The cell cycle was arrested obviously in G(0)/G(1) phase (p < 0.05). The expression of HDAC1 mRNA was inhibited, and the protein level of HDAC1 was down-regulated, while the histone H3/H4 acetylation was up-regulated in U266 cells. It is concluded that the VPA can inhibit cell proliferation of U266 and induce G(0)/G(1) phase arrest. The increase of histone H3/H4 acetylation resulting from inhibiting HDAC1 by VPA might be considered as a possible mechanism.
Acetylation
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drug effects
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Cell Cycle
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drug effects
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Cell Line, Tumor
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Cell Proliferation
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drug effects
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Histone Deacetylase 1
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metabolism
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Histone Deacetylase Inhibitors
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pharmacology
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Histones
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metabolism
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Humans
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Multiple Myeloma
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metabolism
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Valproic Acid
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pharmacology
8.Effect of histone acetylation/deacetylation imbalances on key gene of planar cell polarity pathway.
Hong-Yu DUAN ; Yi ZHANG ; Kai-Yu ZHOU ; Chuan WANG ; DA-Jian QIU ; Yi-Min HUA
Chinese Journal of Contemporary Pediatrics 2017;19(4):475-483
OBJECTIVETo investigate the effect of histone acetylation/deacetylation imbalances on embryonic hearts of mice and its effect on key genes of planar cell polarity (PCP) pathway-Vangl2, Scrib and Rac1 in H9C2 cells.
METHODSForty pregnant C57/B6 mice were randomly assigned into three groups: blank group (n=10), vehicle group (n=10), and valproic acid (VPA)-treated group (n=20). In the VPA-treated group, VPA, a histone deacetylase (HDAC) inhibitor, was administered to each individual dam intraperitoneally at a single dose of 700 mg/kg on embryonic day 10.5 (E10.5). The vehicle and blank groups received equivalent saline or no interventions, respectively. Dams were sacrificed on E15.5, and death rates of embryos were evaluated. Subsequently, embryonic hearts of survival fetus were removed to observe cardiac abnormalities by hematoxylin-eosin (HE) staining. H9C2 cells were cultured and allotted to the blank, vehicle, and VPA-treated groups: the VPA treated group received VPA exposure at concentrations of 2.0, 4.0 and 8.0 mmol/L; the vehicle and blank groups received equivalent saline or no interventions, respectively. HDAC1-3 as well as Vangl2, Scrib and Rac1 mRNA and protein expression levels were determined by quantitative real-time PCR and Western blot, respectively. The total HDAC activity was analyzed by colorimetric assay.
RESULTSThe fetus mortality rate after VPA treatment was 31.7%, with a significantly higher rate of cardiac abnormalities in comparison with the controls (P<0.05). In comparison with the blank and vehicle groups, HDAC1 mRNA was significantly increased at various concentrations of VPA treatment at all time points of exposure (P<0.05), together with a reduction of protein level after 48 and 72 hours of exposure (P<0.05). The inhibition of HDAC2 mRNA after various concentrations of VPA incubation was pronounced at 24 hours of exposure (P<0.05), while the protein levels were reduced at all time points (P<0.05). HDAC3 mRNA was prominently induced by VPA (4.0 and 8.0 mmol/L) at all time points of treatment (P<0.05). In contrast, the protein level was inhibited after VPA treatment (P<0.05). In comparison with the blank and vehicle groups, Vangl2 mRNA as well as Scrib mRNA/protein expression levels were markedly reduced after 48 and 72 hours of VPA treatment (P<0.05), together with a reduction of protein level in Vangl2 at 72 hours (P<0.05). Compared with the blank and vehicle groups, a significant repression in the total HDAC activity was observed in the VPA-treated group at concentrations of 4.0 and 8.0 mmol/L after 24 hours of treatment (P<0.05), and the effect persisted up to 48 and 72 hours, exhibiting pronounced inhibition at all concentrations (P<0.05).
CONCLUSIONSVPA might result in acetylation/deacetylation imbalances by inhibiting HDAC1-3 protein expression and total HDAC activity, leading to the down-regulation of mRNA and protein expression of Vangl2 and Scrib. This could be one of the mechanisms contributing to congenital heart disease.
Acetylation ; Animals ; Cell Polarity ; Cells, Cultured ; Fetal Heart ; drug effects ; metabolism ; Heart Defects, Congenital ; etiology ; Histone Deacetylase 1 ; genetics ; Histone Deacetylase 2 ; genetics ; Histones ; metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins ; genetics ; RNA, Messenger ; analysis ; Valproic Acid ; pharmacology
9.Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain.
Fan YANG ; Yan YANG ; Yan WANG ; Fei YANG ; Chun-Li LI ; Xiao-Liang WANG ; Zhen LI ; Jun CHEN
Acta Physiologica Sinica 2015;67(5):447-454
To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.
Animals
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Bee Venoms
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administration & dosage
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Benzamides
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pharmacology
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Epigenesis, Genetic
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Histone Deacetylase 1
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genetics
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metabolism
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Histone Deacetylase 2
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genetics
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metabolism
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Histone Deacetylase Inhibitors
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pharmacology
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Hot Temperature
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Hyperalgesia
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drug therapy
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Inflammation
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drug therapy
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Injections, Subcutaneous
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Nociception
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Pain
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chemically induced
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drug therapy
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Pain Measurement
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Pyridines
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pharmacology
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Pyrimidines
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pharmacology
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Rats
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Rats, Sprague-Dawley
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Up-Regulation
10.Acetylation of hepatic histone H3 in rats with intrauterine growth retardation.
Xiao-Mei LIU ; Hai-Lan ZHANG ; Wei-Wei SONG ; Yi-Sheng JIAO ; Yan LU
Chinese Journal of Contemporary Pediatrics 2009;11(9):753-756
OBJECTIVETo investigate the effects of intrauterine growth retardation (IUGR) caused by malnutrition during pregnancy on the acetylation of histone H3 and expression of histonedeacetylase1(HDAC1) in the hepar of the adult offspring and to explore the relationship between them.
METHODSMale 8-week-old offspring from maternal protein-malnutrition dams were studied. The expression of HDAC1 mRNA in the hepar was measured by fluorescent quantization RT-PCR. The levels of hepatic nuclear HDAC1 protein and acetylation of histone H3/K9 were assessed by Western blot.
RESULTSThe hepatic HDAC1 mRNA expression in IUGR rats was reduced to 54% of that of normal control rats (t=2.042, p<0.05). A decline in nuclear expression of HDAC1 protein (438 +/- 47) was also noted when compared with normal controls (1,128 +/- 110) (t=2.179, p<0.05). In contrast, the percentage of acetylated histone H3/K9 in IUGR rats (17.3 +/- 1.6%) increased significantly compared with that of normal control rats (10.5 +/- 1.2%) (t=3.597, p<0.01). The level of acetylated histone H3/K9 was negatively correlated with the HDAC1 protein concentration (r=-0.781, p<0.01).
CONCLUSIONSIncreased hepatic acetylation of histone H3 in the IUGR offspring might be caused by decreased HDAC1 expression in nuclear protein. This may contribute to the transcription change of some genes in the hepar.
Acetylation ; Animals ; Female ; Fetal Growth Retardation ; metabolism ; Histone Deacetylase 1 ; analysis ; genetics ; Histones ; metabolism ; Liver ; metabolism ; Male ; Pregnancy ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar