Global Proteomic Analysis of Lysine Lactylation in Placentae from Severe Preeclampsia and Normal Pregnancies
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ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Rong Zhou
PROVIDER: PXD063047 | iProX | Thu Apr 17 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Background: Mortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries. The placenta is central to the etiology of PE. However, how and to what extent the placenta contributes to worse PE outcomes in persons of African ancestry is yet to be fully elucidated. Objective: We aimed to identify molecular pathways that are unique or enriched in placentas of parturient persons of African ancestry with PE with severe features (sPE) compared to those of Asian and European ancestry with sPE. Study design: Bulk RNA sequencing was performed on 50 placentas from parturient persons with sPE of African (n=9), Asian (n=18) and European (n=23) ancestries and 73 normotensive controls of African (n=9), Asian (n=15) and European (n=49) ancestries. Results: Metabolism, hormone regulation and hypoxia/angiogenesis genes, previously described to be upregulated in PE, including: LEP, PAPPA2, INHA, FSTL3, FLT1, PHYHIP and ENG, were upregulated in sPE across ancestries, with high expression of FSTL3 being additionally associated with intrauterine growth restriction (p<.0001). Notably, LEP, FLT1 and PHYHIP were more highly upregulated in sPE placentas from parturient persons of African versus Asian ancestry. Genes associated with allograft rejection and adaptive immune response were selectively upregulated in placentas from African ancestry parturitions and not in those of Asian and European ancestries. Among the allograft rejection/adaptive immune response genes, IL3RA was of particular interest because the patient with the highest placental IL3RA level, a woman of African ancestry with IL3RA levels 4.5-fold above the average for African ancestry parturitions with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients of Asian and European ancestries with the highest IL3RA levels for their ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p=.0005). Conclusions: African ancestry parturitions are associated with higher placental upregulation of metabolism (LEP) and hypoxia/angiogenesis (FLT1) genes, and selective upregulation of allograft rejection/adaptive immune response genes, including IL3RA. High placental expression of IL3RA may predict worse maternal cardiovascular outcomes, including peripartum cardiomyopathy. Studies evaluating placental IL3RA levels in peripartum cardiomyopathy cohorts are therefore warranted, as are broader studies evaluating placental factors in maternal cardiovascular outcomes postpartum.
2023-11-09 | GSE234729 | GEO
Project description:Preeclampsia (PE), which affects ~8% of first pregnancies, is associated with faulty placentation. Extravillous cytotrophoblasts (CTBs) fail to differentiate properly, contributing to shallow uterine invasion and deficient spiral artery remodeling. We studied the effects of severe PE (sPE) on the smooth chorion portion of the fetal membranes. The results showed a significant expansion of the CTB layer. The cells displayed enhanced expression of stage-specific antigens that extravillous CTBs normally up regulate as they exit the placenta. Transcriptomics revealed the dysregulated expression of many genes (e.g., placental proteins, markers of oxidative stress). We confirmed a sPE-related increase in production of PAPPA1, which releases IGF-1 from its binding protein. IGF1 enhanced proliferation of smooth chorion CTBs (schCTB), a possible explanation for expansion of this layer, which may partially compensate for the placental deficits.
2016-12-10 | GSE91189 | GEO
Project description:Dysregulation of Th17 differentiation was implicated in multiple inflammatory and autoimmune diseases including autoimmune uveitis. In the current study, we have provided evidence indicating that lactate-derived lactylation plays important roles in regulating Th17 differentiation. The lactylation level of CD4+ T cells was upregulated in EAU mice and inhibiting lactylation resulted in impaired EAU progression. We characterized the global lactylome of CD4+ T cells of normal and EAU mice. We found that the differentially lactylated proteins were enriched in pathways related to immune responses including leukocyte differentiation. Importantly, our results show that the lactylation level of Ikzf1 (K164) functions in regulating Th17 differentiation by differentially modulating gene expression patterns which are related to CD4+ T cell differentiation by CUT& Tag analysis. In view of the above mentioned well-documented evidence, Ikzf1 lactylation might represent an important regulator for Th17 differentiation in autoimmune uveitis.
2023-08-28 | GSE226678 | GEO
Project description:In preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placenta’s role has been a focus. We hypothesized that decidual defects are an important determinant of the placental phenotype. We isolated (human) endometrial stromal cells (hESCs) from non-pregnant donors with a prior pregnancy that was complicated by severe PE (sPE). Versus controls, they failed to decidualize as demonstrated by morphological criteria and the analysis of stage-specific antigens. These results were bolstered by showing that they were transcriptionally inert. Additionally, we used laser microdissection to isolate the decidua from tissue sections of the maternal-fetal interface. Transcriptional profiling revealed sPE-associated defects in gene expression. Also, decidual cells from sPE patients, which de-differentiated in vitro, failed to re-decidualize in culture. Immediately following isolation they released factors that inhibited CTB invasion, linking a possible cause to a known effect. These data suggested that failed decidualization is an important contributor to down regulated CTB invasion in sPE. Diagnosis of this defect prior to pregnancy would enable therapies that are designed to improve decidualization, a novel strategy for prevention.
2017-02-08 | GSE94643 | GEO
Project description:In the present study, we aimed to discern the preconception decidual transcriptomic signature associated with in vivo defective decidualization in women who suffered sPE in a previous pregnancy. First, we performed a comparative global transcriptional profiling of endometrium from women who developed sPE in a previous pregnancy and from women who never have had sPE. Then, we selected those genes that were significantly deregulated 1.4-fold higher (FDR<0.05) and have an EntrezID code. As a result, we formulate a transcriptional signature associated with defective decidualization composed by 120 genes.
2021-10-06 | GSE172381 | GEO
Project description:Preeclampsia is a common complication of pregnancy that affects 4-5% of pregnant women around the world. At present, there is a lack of early identification of high-risk patients of preeclampsia in clinical practice, which restricts the development of disease prevention and treatment. Previous studies have indicated that plasma exosomal miRNAs in pregnant women could serve as biomarkers of preeclampsia, but few is focused on exosomal miRNAs from preeclampsia pregnancy with severe features(sPE). Therefore, we detected and compared the plasma exosomal miRNA profiles between normal pregancy and sPE to explore potential biomarkers and pathogenic mechanisms of sPE.
2021-11-30 | GSE175807 | GEO
Project description:Endometrial decidualization resistance (DR) is implicated in various gynaecological and obstetric conditions. Employing a multi-omic strategy, we unraveled the cellular and molecular characteristics of DR in patients that have suffered severe preeclampsia (sPE). Morphological analysis unveiled significant glandular anatomical abnormalities, confirmed histologically. Single-cell RNA sequencing (scRNA-seq) of endometrial samples from sPE cases (n=11) and controls (n=12) revealed sPE-associated shifts in cell composition, manifesting as a stromal mosaic state characterized by proliferative stromal cells (MMP11, SFRP1+) alongside IGFBP1+ decidualized cells, with concurrent epithelial mosaicism and a dearth of epithelial-stromal transition associated with decidualization. Cell-cell communication network mapping underscored aberrant crosstalk among specific cell types, implicating crucial pathways such as endoglin and WNT. Spatial transcriptomics in a replication cohort validated DR-associated features. Laser capture microdissection/mass spectrometry in a second replication cohort corroborated several scRNA-seq findings, notably the absence of stromal to epithelial transition at a pathway level, indicating disrupted response to steroid hormones, particularly estrogens. These insights shed light on potential molecular mechanisms underpinning DR pathogenesis in the context of sPE.
2024-10-16 | GSE265862 | GEO
Project description:To obtain the global landscape of lactylation in hypoxia-treated RCC cells, we treated cells with 24 h hypoxia to induce maximum amount of hyperlactylated proteins and performed proteome and lactylome detection upon ACHN cells. Presented here is the raw data for the lactylome.
2025-07-18 | PXD053029 | Pride
Project description:After injury, muscles require fully functional macrophages to recover completely. During muscle regeneration, macrophages transition from a pro-inflammatory to a pro-restorative phenotype ensures the proper regeneration. Lactate is a crucial molecule for muscle-residing macrophage polarisation. Histone lactylation, a direct derivative of lactate, has been implicated in macrophage polarisation in vitro . In this work, we show for the first time that macrophages recruited to the muscle after ischemic injury modify their histone lactylome between 2 and 4 days post injury. Absolute histone lactylation levels increase significantly. Although subtly, also the genomic enrichment of H3K18la changes from 2 to 4 days post injury and this correlates with gene expression changes. Interestingly, we find that H3K18la genomic enrichment changes from day 2 to day 4 post injury are predictive for gene expression changes later in time, from day 4 to day 7, rather than being a reflection of past gene expression changes from day 1 to day 2. Our results suggest that histone lactylation dynamics are functionally important for the resolving action of macrophages during muscle regeneration.
2024-04-08 | GSE254128 | GEO
Project description:After injury, muscles require fully functional macrophages to recover completely. During muscle regeneration, macrophages transition from a pro-inflammatory to a pro-restorative phenotype ensures the proper regeneration. Lactate is a crucial molecule for muscle-residing macrophage polarisation. Histone lactylation, a direct derivative of lactate, has been implicated in macrophage polarisation in vitro . In this work, we show for the first time that macrophages recruited to the muscle after ischemic injury modify their histone lactylome between 2 and 4 days post injury. Absolute histone lactylation levels increase significantly. Although subtly, also the genomic enrichment of H3K18la changes from 2 to 4 days post injury and this correlates with gene expression changes. Interestingly, we find that H3K18la genomic enrichment changes from day 2 to day 4 post injury are predictive for gene expression changes later in time, from day 4 to day 7, rather than being a reflection of past gene expression changes from day 1 to day 2. Our results suggest that histone lactylation dynamics are functionally important for the resolving action of macrophages during muscle regeneration.
2024-04-08 | GSE254129 | GEO