Epigenetic modification of IGF2/H19 imprinting control region regulates PGC-1α/PI3K/AKT2 pathway in a rat model of intrauterine growth restriction.
10.1097/CM9.0000000000003324
- Author:
Lihong LIAO
1
;
Xiuyun ZHOU
1
;
Meihui ZHANG
1
;
Tulian LIN
1
;
Wenjun LONG
1
;
Yaqin YAN
1
;
Qin NING
2
;
Xiaoping LUO
1
Author Information
1. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
2. Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
- Publication Type:Journal Article
- From:
Chinese Medical Journal
2024;138(19):2472-2480
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Intrauterine growth restriction (IUGR) is associated with adverse metabolic outcomes during adulthood. Histone modifications and changes in DNA methylation-affected genes are important for fetal development. This study aimed to confirm the epigenetic mechanisms in IUGR.
METHODS:IUGR models were established in Sprague-Dawley rats using a maternal nutritional restriction approach during pregnancy. The abundance of insulin-like growth factor 2 (IGF2), phosphoinositide 3-kinase (PI3K), AKT serine/threonine kinase 2 (AKT2), and PPAR gamma coactivator 1 alpha (PGC-1α) was examined by real-time polymerase chain reaction (RT-PCR) and Western blotting analysis. Chromatin immunoprecipitation RT-PCR was employed to analyze histone modification in CCCTC-binding factor (CTCF)1-4 binding sites of the IGF2/H19 imprinting control region (ICR). The methylation states of CTCF1-4 binding sites were studied by pyrosequencing.
RESULTS:The IUGR models were constructed successfully. IGF2 mRNA abundance in the placenta, fetal liver, and newborn liver was decreased in the IUGR group (P <0.01). Meanwhile, as compared with the control group, the expression levels of AKT2, PI3K, and PGC-1α were lower in newborn and 8-week-old livers in the IUGR group (P <0.05). In addition, knocking down IGF2 reduced the protein expression levels of AKT2-P and PGC-1α (P <0.05). In CTCF binding sites 1-4 of the IGF2/H19 ICR, AcH3 enrichment was significantly lower in CTCF1-3 in newborn and 8-week-old IUGR rats. H3K4me3 enrichment was significantly lower in the CTCF1-4 of newborn and 8-week-old IUGR groups (P <0.01). H3K9me2 enrichment was significantly higher in the IUGR group (P <0.01). The CpG dinucleotide methylation levels of CTCF1 and CTCF3, but not those of CTCF2 and CTCF4 binding sites in IUGR rat fetal, 4-week old, and 8-week-old livers decreased significantly (P <0.05).
CONCLUSION:The methylation status and histone modification in the IGF2/H19 ICR are related to growth and lipid metabolism via the PGC-1α/PI3K/AKT2 pathway in IUGR rats.
