Prenatal caloric restriction enhances DNA methylation and MeCP2 recruitment with reduced murine placental glucose transporter isoform 3 expression.
Diminished transplacental glucose transport plays an important role in prenatal calorie restriction (CR) induced reduction in fetal growth. Fetal growth restriction (FGR) has an impact in shaping the adult phenotype with transgenerational implications. To understand the mechanisms underlying prenatal CR-induced transplacental glucose transport, we examined the epigenetic regulation of placental glucose transporter (Glut1 and Glut3) expression. We restricted calories by 50% in C57BL6 pregnant mice from gestational days 10 to 19 (CR; n=8) vs. controls (CON; n=8) and observed a 50% diminution in placental Glut3 expression (P<.05) with no effect on Glut1 expression by reverse transcription and quantitative real-time polymerase chain reaction (PCR). CR enhanced DNA methylation of a CpG island situated ~1000 bp upstream from the transcriptional start site of the glut3 gene, with no such effect on the glut1 gene as assessed by methylation-sensitive PCR and bisulfite sequencing. Chromatin immunoprecipitation (ChIP) assays demonstrated enhanced MeCP2 binding to the CpG island of the glut3 gene in response to CR vs. CON (P<.05). Sequential ChIP demonstrated that enhanced MeCP2 binding of the glut3-(m)CpG island enhanced histone deacetylase 2 recruitment (P<.05) but interfered with Sp1 binding (P<.001), although it did not affect Sp3 or Creb/pCreb interaction. We conclude that late-gestation CR enhanced DNA methylation of the placental glut3 gene. This epigenetic change augmented specific nuclear protein-DNA complex formation that was associated with prenatal CR-induced reduction of placental glut3 expression and thereby transplacental glucose transport. This molecular complex provides novel targets for developing therapeutic interventions aimed at reversing FGR.
Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center of UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA.
Amit
A
Ganguly
Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center of UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA; Department of General Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Yongjun
Y
Chen
Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center of UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA.
Bo-Chul
BC
Shin
Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center of UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA. Electronic address: sdevaskar@mednet.ucla.edu.
Sherin U
SU
Devaskar
D000818:Animals; D001483:Base Sequence; D031204:Caloric Restriction; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers; D005260:Female; D051274:Glucose Transporter Type 3 / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction
D017931:DNA Primers; D051274:Glucose Transporter Type 3; D008780:Methyltransferases
Epigenetics; Fetal growth restriction; Histone deacetylases; Sp1 transcription factor