Fetal erythropoiesis and hemoglobin regulation in the context of maternal obesity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE303768 | GEO | 2026/06/25
REPOSITORIES: GEO
Similar Datasets
Project description:The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly linked to rising obesity rates. Maternal obesity (MO) increases offspring susceptibility to metabolic disorders, including MASLD. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a heterochromatin hallmark, silences gene programs dispensable for differentiated cell types. This study investigated how MO influences sex-specific gene expression and chromatin architecture in offspring liver. Female mice consumed a Western-style or control diet pre-pregnancy and throughout gestation/lactation. Offspring were weaned at 3 weeks and transitioned to chow for five weeks. At 3 weeks, liver transcriptomes of control offspring were similar between sexes. However, MO significantly disrupted hepatic gene expression in both sexes, dysregulating hundreds of genes and altering H3K9me3 binding. By 8 weeks, with sexual maturity, control offspring showed substantial sex-based gene expression divergence, predominantly genes involved in immune response, cell adhesion, xenobiotic detoxification, cholesterol metabolism, and lipid partitioning. Thousands of differentially bound H3K9me3 peaks were also observed between 3 and 8 weeks, with many on the female X chromosome. Remarkably, by 8 weeks, MO offspring showed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes, emphasizing the persistent impact of maternal diet on the genomic and metabolic landscape. This study highlights inherent sex differences in liver gene expression and suggests H3K9me3's role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by postnatal dietary normalization.
2025-11-01 | GSE304113 | GEO
Project description:The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly linked to rising obesity rates. Maternal obesity (MO) increases offspring susceptibility to metabolic disorders, including MASLD. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a heterochromatin hallmark, silences gene programs dispensable for differentiated cell types. This study investigated how MO influences sex-specific gene expression and chromatin architecture in offspring liver. Female mice consumed a Western-style or control diet pre-pregnancy and throughout gestation/lactation. Offspring were weaned at 3 weeks and transitioned to chow for five weeks. At 3 weeks, liver transcriptomes of control offspring were similar between sexes. However, MO significantly disrupted hepatic gene expression in both sexes, dysregulating hundreds of genes and altering H3K9me3 binding. By 8 weeks, with sexual maturity, control offspring showed substantial sex-based gene expression divergence, predominantly genes involved in immune response, cell adhesion, xenobiotic detoxification, cholesterol metabolism, and lipid partitioning. Thousands of differentially bound H3K9me3 peaks were also observed between 3 and 8 weeks, with many on the female X chromosome. Remarkably, by 8 weeks, MO offspring showed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes, emphasizing the persistent impact of maternal diet on the genomic and metabolic landscape. This study highlights inherent sex differences in liver gene expression and suggests H3K9me3's role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by postnatal dietary normalization.
2025-11-01 | GSE304112 | GEO
Project description:ETO2 functions as a transcription repressor and is required for the embryonic erythropoiesis and the hemoglobin switch. To gain insight into ETO2 regulatory function during human erythropoiesis, we performed RNA-seq for WT and ETO2 KO K562 cells and found that up-regulated genes upon ETO2 loss in human cells included many markers of mature erythroid cells EPB42, ALAS2, GYPA and SLC25a37. Notably, the α-globin genes (HBA1, HBA2 and HBZ) and embryonic and fetal β-globin genes (HBE1, HBG1, and HBG2) were significantly increased after deletion of ETO2. By contrast, deletion of ETO2 down-regulated the transcription factor genes (ETS1, KLF8 and SOX6) which play a negative role in globin gene expression and hemoglobin synthesis. To further explore different domain function of ETO2, we have analyzed our RNA-seq data from domain deletion cell lines compared to the cell line expressing wild type ETO2. Generally, 702 genes were found to co-regulated by three domain function of ETO2. Interestingly, the regulation of fetal globin genes, erythroid regulator (SOX5) as well as epigenetic factor (HDAC7) is required by three domain function of ETO2. During mouse embryonic erythropoiesis, our FACS-sorted and normal RNA-seq data in E14.5 fetal liver cells indicated that eto2 promoted a critical developmental transition and played an important role in globin switch from embryonic to adult β-globin transcription since its function is essential for key regulators (PU.1, BCL11A and ZBTB7A) and globin genes (Hbb-y and Hba-x) regulation.
2020-08-25 | GSE142226 | GEO
Project description:Over 40% of pregnant American women are obese which negatively affects fetal development with long-term consequences for offspring health. Maternal obesity (MO) leads to fibrotic infiltration in skeletal muscle, brown adipose tissue, and other tissues/organs of offspring, but mechanisms remain to be defined. Using a mouse model of diet-induced obesity and unbiased single-cell RNA-sequencing (scRNA-seq), we tested the effeCONs of MO on embryonic fibrogenesis, which serves as the source of fibrogenic and stromal cells in adults. Embryonic somatic tissues were obtained at E9.5, E11.5 and E13.5 of control (CON) and MO mice. Using unsupervised clustering of scRNA-seq data, we identified three major cell clusters with increasing fibrogenic capacity. Compared to CON, the population of fibrogenic cells increased dramatically due to MO, correlated with the elevated expression of transforming growth factor β (Tgfb) and paired related homeobox 1 (Prrx1), as well as fibrogenic genes.
2024-12-12 | GSE278631 | GEO
Project description:PFAS are persistent man-made chemicals considered to be emerging pollutants, with PFOA, PFOS, and PFHxS having associations with liver toxicity and steatosis. PFOA, PFOS, and PFHxS can undergo placental/lactational transfer, however, little is known about the impact of PFAS mixtures during the developmental window, nor maternal diet on PFAS adverse effects. It was hypothesized that gestational/lactational PFAS exposure would alter the pup liver proteome. The work herein evaluated the liver proteome in offspring, identifying potential biochemical/signaling pathways altered via maternal PFAS exposure. Timed-pregnant CD-1 dams were fed a standard chow or 60% kcal high-fat diet. From GD1 until PND20, dams were orally gavaged daily with either 0.5% Tween 20, individual PFOA, PFOS, PFHxS at 1 mg/kg, or a mixture (1 mg/kg each, totaling 3 mg/kg). Livers were collected from PND21 offspring and SWATH-MS pro-teomics was performed. IPA analysis revealed disease and biological function pathways involved in liver damage, xenobiotics, and lipid regulation were modulated by PFAS exposure in the PND21 liver: lipid transport, storage, oxidation, and synthesis, xenobiotic metabolism and transport, liver damage and inflammation, and fatty acid metabolism, oxidation and transport. This indicates the pup liver proteome is altered via maternal exposure and predisposes the pup to metabolic dysfunctions.
2024-05-09 | PXD052106 | Pride
Project description:The liver is a major site for synthesis, storage and redistribution of carbohydrates, proteins and lipids. In addition, it is well-known that maternal obesity (MO) increases risk of offspring cardiovascular disease (CVD), diabetes and obesity. However, the mechanisms by which the MO intrauterine environment predisposes offspring to CVD and metabolic dysregulation are unknown. The goal of this study was to assess the impact of MO on primate fetal liver and identify underlying molecular mechanisms by which MO increases disease risk. The goal of this study was to identify candidate molecular mechanisms underlying MO in the near-term NHP fetal liver. This is the first study of NHP fetal MO livers using unbiased transcriptome analysis to quantify hepatic gene expression, identify dysregulated signaling pathways and potential miRNAs regulating the disrupted metabolic processes. Unbiased gene (arrays) and microRNA (miRNA; small RNA-Seq) abundances were quantified in near-term (0.9 Gestation (0.9G)) baboon fetal livers (control (CON) = 6; MO = 5) and subjected to pathway and network analyses (GeneSifter, Ingenuity® Pathway Analysis (IPA)) to identify a coordinated molecular response to MO. Lipid and glycogen content (CON = 16; MO = 16) were quantified by Computer Assisted Stereology Toolbox (CAST) in 0.9G livers.Pairwise comparisons showed 933 differentially expressed genes between CON and MO livers: 350 genes were upregulated and 583 were downregulated. Pathway analysis revealed upregulation of Wnt/β-catenin signaling and downregulation of tricarboxylic acid (TCA) cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO fetal livers compared with CON. Inversely expressed miRNAs that target genes in these pathways provide additional support for the importance of these pathways in fetal liver metabolic regulation. Consistent with the observed pathway changes in MO, we found hepatic lipid content was threefold greater in MO than CON fetal livers (p=0.02). Molecular genetic analyses of CON and MO fetal baboon livers revealed dysregulation of Wnt/β-catenin signaling, TCA cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO livers, all of which are central to fatty acid metabolism and lipid storage. The marked lipid accumulation in MO fetal livers supports our hypothesis that dysregulation of these pathways detrimentally impacts lipid management. Furthermore, our findings demonstrate the detrimental impact of MO on fetal liver development and suggest impaired hepatic function prior to birth.
2018-12-26 | GSE99717 | GEO
Project description:Background: Congenital heart disease (CHD) is a leading cause of death in newborns, yet many of its molecular mechanisms remain unknown. Both maternal obesity and diabetes increase the risk of CHD in offspring, with recent studies suggesting these conditions may have distinct teratogenic mechanisms. The global prevalence of obesity is rising, and while maternal obesity is a known risk factor for fetal CHD, the specific mechanisms are largely unexplored. Methods: We used a murine model of diet-induced maternal obesity, without diabetes, to produce dams that were overweight but had normal blood glucose levels. Embryos were generated and their developing hearts analyzed. Transcriptome analysis was performed using single-nuclei (snRNAseq) and bulk RNA sequencing (RNA-seq). Global and phospho-enriched proteome analysis was performed using tandem-mass tag mass spectroscopy (TMT-MS). Immunobloting and histologic evaluation were also performed. Results: Analysis revealed disrupted oxidative phosphorylation and reactive oxygen species formation, with reduced antioxidant capacity, evidenced by downregulation of genes Sod1 and Gp4x, and disrupted Hif1a signaling. Evidence of oxidative stress, cell death signaling, and alteration in Rho GTPase and actin cytoskeleton signaling was also observed. Genes involved in cardiac morphogenesis, including Hand2, were downregulated, and fewer mature cardiomyocytes were present. Histologic analysis confirmed increased cardiac defects in embryos exposed to maternal obesity. Conclusion: These findings demonstrate maternal obesity alone can result in cardiac defects through mechanisms similar to those associated with maternal hyperglycemia. This study provides valuable insights into the role of maternal obesity, a growing and modifiable risk factor, in the development of the most common birth defect, CHD.
2025-06-30 | PXD062087 | Pride
Project description:We have ablated TAF10 in the erythroid compartment only by crossing the TAF10lox mice with the EpoR-Cre mice and we have studied the development of the erythroid cells in vivo. TAF10 ablation led to embryonic death at E13.5 while at E12.5 there was a clear developmental defect which was reflected in the transcriptional profile of the fetal liver cells. Gata1-target genes were mostly affected and were responsible for the lethal phenotype. mRNA from E12.5 fetal livers of TAF10lox/KO:EpoR-Cre+/- (TAF10KO) mice, TAF10HET and WT mice was profiled by NGS (Illumina).
2015-04-21 | E-GEOD-68083 | biostudies-arrayexpress
Project description:Maternal obesity in mice negatively affects placental functionand maternal and fetal liver function. We performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess to identify changes in molecular pathways that might promote diseases in adulthood.
2019-01-24 | PXD011722 | Pride
Project description:The serine threonine kinase Stk40 has been shown to involve in mouse embryonic stem cell differentiation, pulmonary maturation and adipocyte differentiation. Here we report that targeted deletion of Stk40 leads to fetal liver hypoplasia and anemia in the mouse embryos. The reduction of erythrocytes in the fetal liver is accompanied by increased apoptosis and compromised erythroid maturation. Stk40-/- fetal liver cells have significantly reduced colony forming units (CFUs) capable of erythroid differentiation, including burst forming unit-erythroid (BFU-E), colony forming unit-erythroid (CFU-E), and CFU-granulocyte, erythrocyte, megakaryocyte and macrophage (CFU-GEMM), but not CFU-granulocyte/macrophages (CFU-GM). Purified Stk40-/- megakaryocyte-erythrocyte progenitors (MEPs) produced substantially fewer CFU-E colonies compared to control cells. Moreover, Stk40-/- fetal liver erythroblasts failed to form normal erythroblastic islands in association with wild type or Stk40-/- macrophages, indicating an intrinsic defect of Stk40-/- erythroblasts. Furthermore, the hematopoietic stem and progenitor cell pool is reduced in Stk40-/- fetal livers but still retains the multi-lineage reconstitution capacity. Finally, analysis of microarray data of E14.5 fetal liver cells suggests a potential role of aberrantly activated TNF-α signaling in Stk40 depletion induced dyserythropoiesis with a concomitant increase in cleaved Caspase-3 and decrease in Gata1 proteins. Altogether, the identification of Stk40 as a regulator for fetal erythroid differentiation, maturation and survival provides new clues to the molecular regulation of erythropoiesis and related diseases.
2017-06-12 | GSE95017 | GEO