Elevated expression of glycolytic genes as a prominent feature of early-onset preeclampsia: insights from integrative transcriptomic analysis

Jie He; Huan Yang; Zheng Liu; Miaomiao Chen; Ying Ye; Yuelan Tao; Shuhong Li; Jie Fang; Jiacheng Xu; Xiafei Wu; Hongbo Qi

doi:10.3389/fmolb.2023.1248771

Elevated expression of glycolytic genes as a prominent feature of early-onset preeclampsia: insights from integrative transcriptomic analysis

Front Mol Biosci. 2023 Sep 25:10:1248771. doi: 10.3389/fmolb.2023.1248771. eCollection 2023.

Authors

Jie He^{1

2

3}, Huan Yang⁴, Zheng Liu^{1

2

3}, Miaomiao Chen⁵, Ying Ye⁶, Yuelan Tao^{1

2

3}, Shuhong Li⁷, Jie Fang^{1

2

3}, Jiacheng Xu^{1

2

3}, Xiafei Wu^{1

2

3}, Hongbo Qi^{1

2

3

8}

Affiliations

¹ Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
² Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.
³ Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
⁴ Department of Obstetrics, Chongqing University Three Gorges Hospital, Chongqing, China.
⁵ Maternal and Child Health Hospital of Hubei Province, Wuhan, China.
⁶ Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁷ Department of Oncology, Chengdu Second People's Hospital, Chengdu, China.
⁸ Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.

Abstract

Introduction: Preeclampsia (PE), a notable pregnancy-related disorder, leads to 40,000+ maternal deaths yearly. Recent research shows PE divides into early-onset (EOPE) and late-onset (LOPE) subtypes, each with distinct clinical features and outcomes. However, the molecular characteristics of various subtypes are currently subject to debate and are not consistent. Methods: We integrated transcriptomic expression data from a total of 372 placental samples across 8 publicly available databases via combat algorithm. Then, a variety of strategies including Random Forest Recursive Feature Elimination (RF-RFE), differential analysis, oposSOM, and Weighted Correlation Network Analysis were employed to identify the characteristic genes of the EOPE and LOPE subtypes. Finally, we conducted in vitro experiments on the key gene HK2 in HTR8/SVneo cells to explore its function. Results: Our results revealed a complex classification of PE placental samples, wherein EOPE manifests as a highly homogeneous sample group characterized by hypoxia and HIF1A activation. Among the core features is the upregulation of glycolysis-related genes, particularly HK2, in the placenta-an observation corroborated by independent validation data and single-cell data. Building on the pronounced correlation between HK2 and EOPE, we conducted in vitro experiments to assess the potential functional impact of HK2 on trophoblast cells. Additionally, the LOPE samples exhibit strong heterogeneity and lack distinct features, suggesting a complex molecular makeup for this subtype. Unsupervised clustering analysis indicates that LOPE likely comprises at least two distinct subtypes, linked to cell-environment interaction and cytokine and protein modification functionalities. Discussion: In summary, these findings elucidate potential mechanistic differences between the two PE subtypes, lend support to the hypothesis of classifying PE based on gestational weeks, and emphasize the potential significant role of glycolysis-related genes, especially HK2 in EOPE.

Keywords: gestational hypertension; microarray; placenta; preeclampsia; single-cell sequencing; transcriptomics.

Grants and funding

This work was made possible by the funding provided by the Joint Funds of the National Natural Science Foundation of China (No. U21A20346) and the General Program of the National Natural Science Foundation of China (No. 82171662).