Maternal obesity disrupts histone modifications mediated by Ezh2 and Ampk interactions and induces cell fate defects during embryonic cortical neurogenesis.
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE256005 | GEO | 2025/03/05
REPOSITORIES: GEO
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Project description:In this study, we have used a rat model of maternal obesity induced by high fat diet (HFD) prior to and during gestation to investigate the cellular and molecular repercussions of maternal obesity on embryonic cortical neurogenesis. Maternal obesity is noted to substantially disrupt neurogenesis, leading not only to imbalances in cell proliferation vs neuronal differentiation ratios but also prompting a shift towards astrogliogenesis. Differentially expressed genes (DEGs) revealed disruptions in key developmental signaling pathways and reduced Akt phosphorylation particularly notable at the E14.5. These changes were associated with epigenetic alterations, mainly the differential expression and phosphorylation of Ezh2 and subsequent changes in global histone modifications. ChIP-seq revealed reduced H3K27me3 at genes upregulated due to maternal obesity which could have resulted from reduced expression and increased phosphorylation of Ezh2 at Thr311. Interestingly Ezh2 also showed increased O-GlcNAcylation in HFD embryos along with increased association with Ampk-Thr172 in accordance with previous studies showing that Ezh2-Thr311p is catalyzed by Ampk. These results led to propose an epigenetic gene regulatory mechanism mediated by Ampk and Ezh2 interactions resulting in reduced H3K27me3 and de-repression of key developmental genes which could have led to cell fate defects observed in the developing embryo brain cortex due to maternal obesity.
2025-03-05 | GSE256004 | GEO
Project description:In this study, we have used a rat model of maternal obesity induced by high fat diet (HFD) prior to and during gestation to investigate the cellular and molecular repercussions of maternal obesity on embryonic cortical neurogenesis. Maternal obesity is noted to substantially disrupt neurogenesis, leading not only to imbalances in cell proliferation vs neuronal differentiation ratios but also prompting a shift towards astrogliogenesis. Differentially expressed genes (DEGs) revealed disruptions in key developmental signaling pathways and reduced Akt phosphorylation particularly notable at the E14.5. These changes were associated with epigenetic alterations, mainly the differential expression and phosphorylation of Ezh2 and subsequent changes in global histone modifications. ChIP-seq revealed reduced H3K27me3 at genes upregulated due to maternal obesity which could have resulted from reduced expression and increased phosphorylation of Ezh2 at Thr311. Interestingly Ezh2 also showed increased O-GlcNAcylation in HFD embryos along with increased association with Ampk-Thr172 in accordance with previous studies showing that Ezh2-Thr311p is catalyzed by Ampk. These results led to propose an epigenetic gene regulatory mechanism mediated by Ampk and Ezh2 interactions resulting in reduced H3K27me3 and de-repression of key developmental genes which could have led to cell fate defects observed in the developing embryo brain cortex due to maternal obesity.
2025-03-05 | GSE255917 | GEO
Project description:Maternal obesity disrupts histone modifications mediated by Ezh2 and Ampk interactions and induces cell fate defects during embryonic cortical neurogenesis.
| PRJNA1077376 | ENA
Project description:Maternal obesity disrupts histone modifications mediated by Ezh2 and Ampk interactions and induces cell fate defects during embryonic cortical neurogenesis. [RNA-seq]
| PRJNA1077385 | ENA
Project description:Maternal obesity disrupts histone modifications mediated by Ezh2 and Ampk interactions and induces cell fate defects during embryonic cortical neurogenesis. [ChIP-Seq]
| PRJNA1077241 | ENA
Project description:Neurodevelopmental disorders have complex origins that manifest early during embryonic growth and are associated with intricate gene regulation dynamics. A perturbed metabolic environment such as hyperglycemia or dyslipidemia, particularly due to maternal obesity, poses a threat to the optimal development of the embryonic central nervous system. Accumulating evidence suggests that these metabolic irregularities during pregnancy may alter neurogenesis pathways, thereby predisposing the developing fetus to neurodevelopmental disorders. One primary mechanism through which such disruptions may occur involves changes in histone modifications resulting from fluctuations in the expression of histone-modifying enzymes or the availability of their substrates. Herein, we have used a rat model of maternal obesity induced by a high-fat diet before and during gestation to investigate the cellular and molecular repercussions of maternal obesity on embryonic cortical neurogenesis. Maternal obesity impairs neurogenesis by reducing cell proliferation, increasing neuronal marker expression, and shifting development toward astrogliogenesis. Differentially expressed genes revealed disruptions in key developmental signaling pathways and reduced AKT phosphorylation, particularly at E14.5. These changes were associated with epigenetic alterations, mainly the differential expression and phosphorylation of EZH2 and subsequent changes in global histone modifications. Chromatin immunoprecipitation sequencing revealed reduced H3K27me3 at genes upregulated due to maternal obesity, which could have resulted from reduced expression and increased phosphorylation of EZH2 at Thr311. Interestingly, EZH2 also showed increased O-GlcNAcylation in high-fat diet embryos along with increased association with AMPK-Thr172 in accordance with previous studies showing that Ampk catalyzes EZH2-Thr311p. These results suggest that an epigenetic gene regulatory mechanism mediated by Ampk and Ezh2 interactions resulted in reduced H3K27me3 and derepression of key developmental genes, which could have led to cell fate changes observed in the developing embryo brain cortex due to maternal obesity.
| S-EPMC11847741 | biostudies-literature
Project description:Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination.
| S-EPMC4704102 | biostudies-literature
Project description:Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain.
| S-EPMC5600197 | biostudies-literature
Project description:Recently, de novo mutations of transcription factor 20 (TCF20) were found in patients with autism by large-scale exome sequencing. However, how TCF20 modulates brain development and whether its dysfunction causes ASD remain unclear. Here, we show that TCF20 deficits impair neurogenesis in mouse. TCF20 deletion significantly reduces the number of neurons, which leads to abnormal brain functions. Furthermore, transcriptome analysis and ChIP-qPCR reveal that the DNA demethylation factor TDG is a downstream target gene of TCF20. As a nonspecific DNA demethylation factor, TDG potentially affects many genes. Combined TDG ChIP-seq and GO analysis of TCF20 RNA-Seq identifies T-cell factor 4 (TCF-4) as a common target. TDG controls the DNA methylation level in the promoter area of TCF-4, affecting TCF-4 expression and modulating neural differentiation. Overexpression of TDG or TCF-4 rescues the deficient neurogenesis of TCF20 knockdown brains. Together, our data reveal that TCF20 is essential for neurogenesis and we suggest that defects in neurogenesis caused by TCF20 loss are associated with ASD.
| S-EPMC7403713 | biostudies-literature
Project description:BACKGROUND: Obesity affects almost one-third of pregnant women and causes many complications, including neural tube defects. It is not clear whether the risk of congenital heart defects, the most common malformations, is also increased. OBJECTIVE: This study was conducted to determine whether obesity is associated with an increased risk of congenital heart defects. DESIGN: A population-based, nested, case-control study was conducted in infants born with congenital heart defects and unaffected controls from the cohort of all births (n = 1,536,828) between 1993 and 2003 in New York State, excluding New York City. The type of congenital heart defect, maternal body mass index (BMI; in kg/m(2)), and other risk factors were obtained from the Congenital Malformations Registry and vital records. Mothers of 7392 congenital heart defect cases and 56,304 unaffected controls were studied. RESULTS: All obese women (BMI > or = 30) were significantly more likely than normal-weight women (BMI: 19-24.9) to have children with a congenital heart defect [odds ratio (OR): 1.15; 95% CI: 1.07, 1.23; P < 0.0001]. Overweight women were not at increased risk (OR: 1.00; 95% CI: 0.94, 1.06). The risk in morbidly obese women (BMI > or = 40) was higher (OR: 1.33; 95% CI: 1.15, 1.54; P = 0.0001) than that in obese women with a BMI of 30-39.9 (OR: 1.11; 95% CI: 1.04, 1.20; P = 0.004). There was a highly significant trend of increasing OR for congenital heart defects with increasing maternal obesity (P < 0.0001). The offspring of obese women had significantly higher ORs for atrial septal defects, hypoplastic left heart syndrome, aortic stenosis, pulmonic stenosis, and tetralogy of Fallot. CONCLUSIONS: Obese, but not overweight, women are at significantly increased risk of bearing children with a range of congenital heart defects, and the risk increases with increasing BMI. Weight reduction as a way to reduce risk should be investigated.
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