Uteroplacental insufficiency affects epigenetic determinants of chromatin structure in brains of neonatal and juvenile IUGR

被引:107
作者
Ke, X
Lei, Q
James, SJ
Kelleher, SL
Melnyk, S
Jernigan, S
Yu, X
Wang, L
Callaway, CW
Gill, G
Chan, GM
Albertine, KH
McKnight, RA
Lane, RH
机构
[1] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT 84158 USA
[2] Univ Calif Los Angeles, Mattel Chidrens Hosp, David Geffen Sch Med, Los Angeles, CA USA
[3] Univ Calif Los Angeles, Mattel Chidrens Hosp, Dept Pediat, Los Angeles, CA USA
[4] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA
[5] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA
关键词
Barker's fetal origins of adult disease hypothesis; zinc; DNA methylation; histone deacetylase; histone acetylation;
D O I
10.1152/physiolgenomics.00093.2005
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Intrauterine growth retardation ( IUGR) increases the risk of neuroendocrine reprogramming. In the rat, IUGR leads to persistent changes in cerebral mRNA levels. This suggests lasting alterations in IUGR cerebral transcriptional regulation, which may result from changes in chromatin structure. Candidate nutritional triggers for these changes include altered cerebral zinc and one-carbon metabolite levels. We hypothesized that IUGR affects cerebral chromatin structure in neonatal and postnatal rat brains. Rats were rendered IUGR by bilateral uterine artery ligation; controls (Con) underwent sham surgery. At day of life 0 (d0), we measured cerebral DNA methylation, histone acetylation, expression of chromatin-affecting enzymes, and cerebral levels of one-carbon metabolites and zinc. At day of life 21 (d21), we measured cerebral DNA methylation and histone acetylation, as well as the caloric content of Con and IUGR rat breast milk. At d0, IUGR significantly decreased genome-wide and CpG island methylation, as well as increased histone 3 lysine 9 (H3/K9) and histone 3 lysine 14 (H3/K14) acetylation in the hippocampus and periventricular white matter, respectively. IUGR also decreased expression of the chromatin-affecting enzymes DNA methyltransferase 1 (DNMT1), methyl-CpG binding protein 2 (MeCP2), and histone deacetylase (HDAC) 1 in association with increased cerebral levels of zinc. In d21 female IUGR rats, cerebral CpG DNA methylation remained lower, whereas H3/K9 and H3/K14 hyperacetylation persisted in hippocampus and white matter, respectively. In d21 male rats, IUGR decreased acetylation of H3/K9 and H3/K14 in these respective regions compared with controls. Despite these differences, caloric, fat, and protein content were similar in breast milk from Con and IUGR dams. We conclude that IUGR results in postnatal changes in cerebral chromatin structure and that these changes are sex specific.
引用
收藏
页码:16 / 28
页数:13
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