Maternal high-fat diet aggravates the development of atherosclerosis in offspring via epigenetic memory (ATAC-Seq CUT&Tag)
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ABSTRACT:
PROVIDER: PRJNA1156764 | ENA |
REPOSITORIES: ENA
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Project description:Maternal exposure to a western-type diet (WD) increases the susceptibility of adult offspring to atherosclerosis. Lining the inner layer of blood vessels, fetus endothelial cells (ECs) become dysfunctional and inflamed in response to risk factors from mother through maternal and fetal blood exchange. However, the mechanism by which maternal WD promotes vascular endothelial dysfunction and atherosclerosis in offspring after adulthood has not been fully clarified. Here, we found that maternal WD exposure sensitized offspring to WD exposure in adulthood of Ldlr-/- mice, significantly increasing atherosclerotic lesions in the aorta and aortic roots, endowed inflammatory memory at the chromatin level and regulated chromatin dynamics by transcription factor AP-1 in mouse aortic ECs. Plasma 27-hydroxycholesterol (27-HC) was significantly increased in maternal blood and transferred into the offspring. Additionally, 27-HC played a crucial role in memory establishment and also acted as a secondary stimulator, amplifying the expression of inflammatory memory factors and enhancing the enrichment of AP-1/p300 and H3K27ac in the binding domain in human ECs. Inhibiting AP-1 binding to chromatin reduced the inflammatory response in human umbilical vein ECs from mother with maternal hypercholesterolemia and the occurrence and development of atherosclerosis in the offspring with maternal WD exposure. Our findings demonstrate that maternal WD aggravating EC dysfunction and atherosclerosis in offspring after adulthood acquires AP-1-associated epigenetic memory to increase chromatin accessibility of inflammatory genes.
2025-01-23 | GSE276350 | GEO
Project description:Maternal exposure to a western-type diet (WD) increases the susceptibility of adult offspring to atherosclerosis. Lining the inner layer of blood vessels, fetus endothelial cells (ECs) become dysfunctional and inflamed in response to risk factors from mother through maternal and fetal blood exchange. However, the mechanism by which maternal WD promotes vascular endothelial dysfunction and atherosclerosis in offspring after adulthood has not been fully clarified. Here, we found that maternal WD exposure sensitized offspring to WD exposure in adulthood of Ldlr-/- mice, significantly increasing atherosclerotic lesions in the aorta and aortic roots, endowed inflammatory memory at the chromatin level and regulated chromatin dynamics by transcription factor AP-1 in mouse aortic ECs. Plasma 27-hydroxycholesterol (27-HC) was significantly increased in maternal blood and transferred into the offspring. Additionally, 27-HC played a crucial role in memory establishment and also acted as a secondary stimulator, amplifying the expression of inflammatory memory factors and enhancing the enrichment of AP-1/p300 and H3K27ac in the binding domain in human ECs. Inhibiting AP-1 binding to chromatin reduced the inflammatory response in human umbilical vein ECs from mother with maternal hypercholesterolemia and the occurrence and development of atherosclerosis in the offspring with maternal WD exposure. Our findings demonstrate that maternal WD aggravating EC dysfunction and atherosclerosis in offspring after adulthood acquires AP-1-associated epigenetic memory to increase chromatin accessibility of inflammatory genes.
2025-01-22 | GSE276351 | GEO
Project description:Maternal high-fat diet aggravates the development of atherosclerosis in offspring via epigenetic memory (SMART-Seq)
| PRJNA1156763 | ENA
Project description:Enhanced prenatal fatty streak formation in human fetuses has been associated with maternal hypercholesterolemia. However, the possible roles of maternal genetic background and in utero environment on development of atherosclerosis in adult life have not been unraveled. We generated genetically identical heterozygous apoE-deficient mice offspring with a different maternal background to study the intrauterine effect of maternal genotype and associated hypercholesterolemia on the developing vascular system. As read out for increased atherosclerosis development in adult life, a constrictive collar was placed around the carotid artery to induce lesion formation. A significant increase in endothelial cell activation and damage was detected in the carotid arteries of heterozygous apoE-deficient fetuses with apoE-deficient mothers compared with offspring from wild type mothers, but no fatty streak formation was observed. Postnatally, all carotid arteries revealed normal morphology. In adult offspring with maternal apoE-deficiency, the constrictive collar resulted in severe lesion (9/10) development compared with no to only minor lesions (2/10) in offspring of wild type mothers. Microarray analysis showed no effect of maternal apoE-deficiency on gene expression in adult offspring. We conclude that maternal apoE-deficiency not only affects fetal arteries, but also increases the susceptibility for development of collar-induced atherosclerosis in adult life. Experiment Overall Design: Crossing of hypercholesterolemic female with normocholesterolemic male and vice versa, determination of susceptabilioty to atherosclerosis in offspring
2008-06-14 | E-GEOD-6134 | biostudies-arrayexpress
Project description:Alternate high fat diet aggravates atherosclerosis through an IL1b-dependent reprogramming of neutrophil progenitors
| PRJNA1061499 | ENA
Project description:We tested if minor changes in maternal non-shivering thermogenesis during pregnancy can severely alter the phenotype of the offspring already in the next generation. Therefore, male offspring of dams lacking the uncoupling protein 1 (UCP1-KO) in the thermogenic brown adipose tissue were analysed. Genome-wide expression profiling identified several alterations in the hepatic transcriptomic landscape, demonstrating that even minor differences in the demand for maternal thermogenesis profoundly and permanently alter hepatic gene activity in the adult offspring. Liver gene expression data of offspring from WT and UCP1-KO dams.
2020-11-09 | GSE145143 | GEO
Project description:We tested if minor changes in environmental temperature during pregnancy can severely alter the phenotype of the offspring already in the next generation. Genome-wide expression profiling of liver samples obtained from adult male mice offspring identified several alterations in the hepatic transcriptomic landscape, thus demonstrating that even minor differences in the demand for maternal thermogenesis profoundly and permanently alter hepatic gene activity in the adult offspring. Liver gene expression data of offspring from dams that were kept at different ambient temperatures (30°C, 23°C, 18°C, 10°C) only during pregnancy.
2020-11-09 | GSE145142 | GEO
Project description:Cecal microbiome of C-, WD- and REV-dams at weaning and in their offspring (C-offspring, WD-offspring, and REV-offspring, respectively) at 4 months.
| PRJEB64354 | ENA
Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, the consequences of an alternate high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue concerning common situations where dietary habits change over time, we developed a novel protocol in athero-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, the overall period of time of exposure to HFD being similar between groups. We showed that alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared to continuous HFD. The pro-atherogenic effect of alternate HFD was also found in Apoe-/-Rag2-/- mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the observed phenotype. Using different complementary in vivo approaches, we found that lipid-rich diet discontinuation in alternate group downregulated Runx1, a negative regulator downstream of TLR-4 pathways. As a result, after re-exposure to HFD, myeloid progenitors were more sensitive to hypercholesterolemia leading to acute differentiation into IL-1b- producing immature neutrophils, which caused a state of emergency myelopoiesis. Consecutively, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1b receptor confirmed that the IL-1b signaling pathway was a major driver of the pro-inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1b neutralizing antibody or inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1b-dependent neutrophil progenitor reprogramming.
2024-04-14 | GSE252604 | GEO
Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, it is common for individuals to change dietary habits over time. The consequences of an alternating high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue, we developed a novel protocol in atherosclerosis-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, while keeping the overall period of exposure to HFD similar between groups. We showed that an alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe 55 -/- mice compared to continuous HFD. This pro-atherogenic effect of alternate HFD was also observed in Apoe-/-Rag2 57 -/- mice lacking T, B, and NKT cells, ruling out the role of the adaptive immune system in the observed phenotype. Employing various complementary in vivo approaches, we discovered that discontinuing HFD in the alternate group downregulated Runx1, a negative regulator of inflammatory signaling pathways in the myeloid lineage. Consequently, after re61 exposure to HFD, myeloid progenitors were primed to respond to HFD re-exposure by differentiating into IL-1-producing immature neutrophils, and inducing a state of emergency myelopoiesis. Subsequently, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1 receptor confirmed that the IL-1 signaling pathway was a major driver of the pro67 inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1 neutralizing antibody or an inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1-dependent neutrophil progenitor reprogramming.
2024-04-23 | GSE254105 | GEO