Hypoxia regulates fibrosis-related genes via histone lactylation in the placentas of patients with preeclampsia

Background: Histone lactylation, a novel epigenetic modification induced by hypoxia and lactate, plays an important role in regulating gene expression. However, the role of histone lactylation in the pathogenesis of preeclampsia remains unknown. Methods: Placentas from preeclamptic patients and control pregnant women were collected for protein immunoassay to detect the expression level of histone lactylation, and two trophoblast cell lines were used to simulate the effect of histone lactylation on genes. Results: We found that lactate and histone lactylation levels were increased in preeclamptic placentas. In vitro, hypoxia was demonstrated to induce histone lactylation by promoting the production of lactate in human-trophoblast-derived cell line (HTR-8/SVneo) and human first-trimester extravillous trophoblast cell line (TEV-1) cells. In addition, 152 genes were found to be upregulated by both hypoxia exposure and sodium l-lactate treatment in HTR-8/SVneo cells. These genes were mainly enriched in the pathways including the response to hypoxia, cell migration and focal adhesion. Among the 152 genes, nine were upregulated in preeclamptic placentas. Most noteworthy, two upregulated fibrosis-related genes, FN1 and SERPINE1, were promoted by hypoxia through histone lactylation mediated by the production of lactate. Conclusions: The present study demonstrated the elevated levels of histone lactylation in preeclamptic placentas and identified fibrosis-related genes that were promoted by histone lactylation induced by hypoxia in trophoblast cells, which provides novel insights into the mechanism of placental dysfunction in preeclampsia.

[1]  Steven J. M. Jones,et al.  Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease. , 2021, Developmental cell.

[2]  Lubo Zhang,et al.  Hypoxia and Mitochondrial Dysfunction in Pregnancy Complications , 2021, Antioxidants.

[3]  Daniel C. Lee,et al.  Identification of Cardiac Fibrosis in Young Adults With a Homozygous Frameshift Variant in SERPINE1. , 2021, JAMA cardiology.

[4]  D. Charnock-Jones,et al.  Placental energy metabolism in health and disease - significance of development and implications for preeclampsia. , 2020, American journal of obstetrics and gynecology.

[5]  V. Shah,et al.  Epigenomic Evaluation of Cholangiocyte TGFβ Signaling Identifies a Selective Role for Histone 3 Lysine 9 Acetylation in Biliary Fibrosis. , 2020, Gastroenterology.

[6]  Zhankui Jia,et al.  MicroRNA-219c-5p regulates bladder fibrosis by targeting FN1 , 2020, BMC Urology.

[7]  Gang Liu,et al.  PAI-1 Regulation of TGF-β1-induced ATII Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages. , 2020, American journal of respiratory cell and molecular biology.

[8]  A. Shilatifard,et al.  Epigenetic modifications of histones in cancer , 2019, Genome Biology.

[9]  R. Jaenisch,et al.  Editing the Epigenome to Tackle Brain Disorders , 2019, Trends in Neurosciences.

[10]  P. Karagianni,et al.  Epigenetic perspectives on systemic autoimmune disease. , 2019, Journal of autoimmunity.

[11]  B. Ren,et al.  Metabolic regulation of gene expression by histone lactylation , 2019, Nature.

[12]  F. Figueras,et al.  Association of plasma lactate concentration at admission of severe preeclampsia to maternal complications. , 2019, Pregnancy hypertension.

[13]  Ha Won Kim,et al.  Epigenetic Regulation of Vascular Diseases. , 2019, Arteriosclerosis, thrombosis, and vascular biology.

[14]  D. Giussani,et al.  Preeclampsia link to gestational hypoxia , 2019, Journal of Developmental Origins of Health and Disease.

[15]  S. Karumanchi,et al.  Preeclampsia: Pathophysiology, Challenges, and Perspectives , 2019 .

[16]  E. George,et al.  Acute Hypoxia and Chronic Ischemia Induce Differential Total Changes in Placental Epigenetic Modifications , 2018, Reproductive Sciences.

[17]  H. Yagi,et al.  Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts Activated by the Transforming Growth Factor-β1 Signaling Pathway. , 2017, The American journal of pathology.

[18]  L. Gladden,et al.  Lactate metabolism: historical context, prior misinterpretations, and current understanding , 2018, European Journal of Applied Physiology.

[19]  E. Dempsey,et al.  Estimating the Cost of Preeclampsia in the Healthcare System: Cross-Sectional Study Using Data From SCOPE Study (Screening for Pregnancy End Points) , 2017, Hypertension.

[20]  I. Darby,et al.  Hypoxia in tissue repair and fibrosis , 2016, Cell and Tissue Research.

[21]  L. Magee,et al.  Pre-eclampsia , 2016, The Lancet.

[22]  A. Shennan,et al.  Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. , 2015, Obstetrics and gynecology.

[23]  D. Subtil,et al.  A case–control study of placental lesions associated with pre‐eclampsia , 2013, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[24]  I. Brosens,et al.  Defective deep placentation. , 2011, Best practice & research. Clinical obstetrics & gynaecology.

[25]  M. Esteller,et al.  Epigenetic modifications and human disease , 2010, Nature Biotechnology.

[26]  S. Tsoi,et al.  Hypoxia and lactate production in trophoblast cells. , 2007, Placenta.

[27]  C. Sibley,et al.  Polarized lactate transporter activity and expression in the syncytiotrophoblast of the term human placenta. , 2004, Placenta.

[28]  S. Yagel,et al.  Regulation of trophoblast invasion: from normal implantation to pre-eclampsia , 2002, Molecular and Cellular Endocrinology.

[29]  T. Nakayama,et al.  Post-transcriptional regulation of Xwnt-8 expression is required for normal myogenesis during vertebrate embryonic development. , 1999, Development.

[30]  W. B. Robertson,et al.  The role of the spiral arteries in the pathogenesis of preeclampsia. , 1972, Obstetrics and gynecology annual.