IUGR disrupts the PPARγ‐Setd8‐H4K20me¹ and Wnt signaling pathways in the juvenile rat hippocampus

Abstract

Intrauterine growth restriction (IUGR) programs neurodevelopmental impairment and long-term neurological morbidities. Neurological morbidities in IUGR infants are correlated with changes hippocampal volume. We previously demonstrated that IUGR alters hippocampal cellular composition in both neonatal and juvenile rat pups in association with altered hippocampal gene expression and epigenetic determinants. PPARγ signaling is important for neurodevelopment as well as epigenetic integrity in the brain via the PPARγ-Setd8-H4K20me1 axis and Wnt signaling. We hypothesized that IUGR would decrease expression of PPARγ, Setd8, and H4K20me1 in juvenile rat hippocampus. We further hypothesized that reduced PPARγ-Setd8-H4K20me1 would be associated with reduced Wnt signaling genes Wnt3a and β-catenin, and wnt target gene Axin2. To test our hypothesis we used a rat model of uteroplacental insufficiency-induced IUGR. We demonstrated that PPARγ localizes to oligodendrocytes, neurons and astrocytes within the juvenile rat hippocampus. We also demonstrated that IUGR reduces levels of PPARγ, Setd8 and H4K20me1 in male and female juvenile rat hippocampus in conjunction with reduced Wnt signaling components in only male rats. We speculate that reduced PPARγ and Wnt signaling may contribute to altered hippocampal cellular composition which, in turn, may contribute to impaired neurodevelopment and subsequent neurocognitive impairment in IUGR offspring.

Integrated Analysis of Summary Statistics to Identify Pleiotropic Genes and Pathways for the Comorbidity of Schizophrenia and Cardiometabolic Disease

“…Consistent with our results, multiple experiments indicated that changed expression level of SETD8 may affect insulinoma cell proliferation (62), hyperglycemic memory (63), and lipid metabolism (64). One study has shown that reducing the expression levels of SETD8 may contribute to altered hippocampal cellular composition, impaired neurodevelopment, and subsequent neurocognitive impairment (65), which are associated with the phenotype of SCZ. GATAD2A is a subunit of the nucleosome remodeling and histone deacetylase (NuRD) complex, which is generally a s s o c i a t e d w i t h e m b r y o n i c d e v e l o p m e n t , c e l l u l a r differentiation, and the repression of transcription (66).…”

The PPARγ‐SETD8 axis constitutes an epigenetic, p53‐independent checkpoint on p21‐mediated cellular senescence

“…We next set out to assess whether the expression changes of SETD8 in response to senescence could be attributed to transcriptional regulation. In this regard, we tested possible involvement of two transcription factors, c‐MYC and PPARγ, which were previously demonstrated to mediate the expression of SETD8 (Wakabayashi et al ., ; Driskell et al ., ; Ke et al ., ). These two factors were chosen also due to their presumed roles in the senescence of various cancer cell lines (Wu et al ., ; Briganti et al ., ).…”

Differential Effects of Intrauterine Growth Restriction on the Regional Neurochemical Profile of the Developing Rat Brain

“…One final consideration when interpreting our data is the effect of IUGR on brain volume or cell density within a given region. Several groups have reported structural brain changes in IUGR that might affect the neurochemical profile for a given region (3,56–58). However, if the changes we observed in this study were due to a reduced brain volume or cell density alone, we would have expected a uniform reduction in neurochemical profiles in all 3 IUGR brain regions.…”