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Hypoxia Inducible Factors (HIF1α and HIF3α) are differentially methylated in preeclampsia placentae and are associated with birth outcomes

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Abstract

Preeclampsia is a placental vascular pathology and hypoxia is known to influence placental angiogenesis. Hypoxia Inducible Factors (HIF1α and HIF3α) mediate the response to cellular oxygen concentration and bind to hypoxia response element of target genes. However the mechanism regulating above activity is not well-understood. We investigated if placental DNA methylation (DNAm) and expression of HIF1α and 3α genes are altered and associated with pre-eclampsia, placental weight and birth outcomes. Using a cohort comprising women with preeclampsia [N = 100, delivering at term (N = 43) and preterm (N = 57)] and normotensive controls (N = 100), we analysed DNAm in HIF1α and 3α, and their mRNA expression in placentae, employing pyrosequencing and quantitative real-time PCR, respectively. We observed significant hypermethylation at cg22891070 of HIF3α in preeclampsia placentae compared to controls (β = 1.5%, p = 0.04). CpG8 in the promoter region of HIF1α, showed marginally significant hypomethylation in preterm preeclampsia compared to controls (β = − 0.15%, p = 0.055). HIF1α expression was significantly lower in preterm preeclampsia compared to controls (mean ± SE = 10.16 ± 2.00 vs 4.25 ± 0.90, p = 0.04). Further, DNAm in HIF1α promoter region was negatively associated with its expression levels (β =  − 0.165, p = 0.024). Several CpGs in HIF1α were negatively associated with placental weight and birth outcomes including birth weight (β range =  − 0.224–0.300) and birth length [β range =  − 0.248 to − 0.301 (p < 0.05 for all)]. Overall, we demonstrate altered DNAm in HIF1α and HIF3α in preeclampsia placentae, also associated with various birth outcomes. Correlation of DNAm in HIF1α and its expression suggests a possible role in the pathogenesis of pre-eclampsia. Further investigations on interactions between HIF1α and HIF3α in preeclampsia would be interesting.

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Data availability

The study data will be available on request subject to approval from the Institutional Ethics Committee and Health Ministry Screening Committee, Govt of India. Methylation data have been placed on the server of the CSIR—Centre for Cellular and Molecular Biology (www.ccmb.res.in) in Hyderabad and can be accessed with permission from the authors.

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Acknowledgements

We thank the pregnant women and their families' willingness to participate in the study and provide informed consent. We thank all members of Mother and Child Health department, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University and members of Genomic Research on Complex diseases group (GRC group), CSIR-CCMB, Hyderabad for helpful discussions and valuable insights.

Funding

The Indian Council of Medical Research—Centre for Advanced Research in Preeclampsia (ICMR-CAR; Grant No. 5/7/1069/13-RCH, dt. 31/03/2017), Ministry of Health and Family Welfare, Government of India, New Delhi, India, sponsored this study. CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Ministry of Science and Technology, Government of India, New Delhi, India, provided further additional funding.

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  1. Lovejeet Kaur

    Present address: Maternal and Child Health (MCH), Translational Health Science and Technology Institute (THSTI), Faridabad, 121001, India

Authors and Affiliations

  1. Genomic Research on Complex Diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, 500007, India

    Lovejeet Kaur, Swati Bayyana & Giriraj R. Chandak

  2. Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune Satara Road, Pune, 411043, India

    Deepali Sundrani, Kinjal Dave, Karuna Randhir & Sadhana Joshi

  3. Department of Gynecology and Obstetrics, Bharati Vidyapeeth Medical College and Hospital, Pune, 411043, India

    Savita Mehendale

  4. CSI Epidemiology Research Unit, Holdsworth Memorial Hospital, Mysore, India

    Kumaran Kalyanaraman

  5. MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK

    Kumaran Kalyanaraman

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Contributions

SJ and GRC conceived and designed the experiments. LK, DS and KD performed the experiments. LK, DS, KR, and KK analyzed the data. SM was involved in recruitment of women. SJ and GC contributed reagents/materials/analysis tools. LK, DS, SB, SJ and GRC wrote the paper and LK was a major contributor. All authors read and approved the final manuscript.

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Correspondence to Giriraj R. Chandak or Sadhana Joshi.

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The authors declare no competing interests.

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The Bharati Vidyapeeth Medical College Institutional Ethics Committee gave approval to this study (Ethics no: BVDUMC/IEC/81A dated 11/04/2018), following which the study was undertaken.

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After receiving written informed consent, patients were recruited at Department of Obstetrics & Gynecology, Bharati Hospital, Pune.

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Kaur, L., Sundrani, D., Dave, K. et al. Hypoxia Inducible Factors (HIF1α and HIF3α) are differentially methylated in preeclampsia placentae and are associated with birth outcomes. Mol Cell Biochem 478, 2309–2318 (2023). https://doi.org/10.1007/s11010-023-04661-y

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