PhD Scientific Days 2023

Molecular Sciences - Posters B

Evolutionary Changes in the Zinc Finger 554 (ZNF554) Locus in Anthropoid Primates: Implications for Deep Placentation and Preeclampsia

Text of the abstract

Introduction: The placenta comprises highly specialized trophoblast cell types, including syncytiotrophoblast and extravillous trophoblast. Their formation and specialization are all governed by transcription factors. One of the largest transcription factor families in the human genome, zinc-finger proteins (ZNFs), plays a vital role in placental development and trophoblast differentiation. ZNF554 was earlier found to be highly expressed in the placenta, where it regulates trophoblastic functions including deep invasion into maternal tissues, a feature uniquely present in humans and inhibited in preeclampsia.
Aim: We investigated how the evolution of the ZNF554 locus affected the regulation of placental ZNF554 expression, trophoblast invasion, and the vulnerability to preeclampsia.
Methods: The evolution of the ZNF554 locus was examined in silico using the USCS Genome Brower. The transcriptional regulation of ZNF554 by ZEB1, ZEB2, and hypoxia was investigated in vitro by luciferase assay. We investigated the neighboring hypoxia-response elements (HREs) located in AluY and their hypermethylation in preeclampsia. For this, we analyzed three CpG deletion clones by luciferase assay.
Results: In primates, the ZNF554 locus evolved through the insertion of primate-specific transposable elements, leading to the establishment of ZEB binding sites and HREs in the 5' flanking region. In humans, the LTR10A elements were multiplicated, which introduced numerous ZEB binding sites into the promoter region. Co-transfection with ZEB1/2 increased reporter activity in extravillous trophoblasts, influenced by oxygen concentration. Deletion of CpG in HREs in AluY decreased reporter activity, suggesting that epigenetic mechanisms regulate decreased ZNF554 expression in preterm preeclampsia.
Conclusion: The study revealed that evolutionary changes in the ZNF554 locus enabled the regulation of ZNF554 expression by hypoxia and ZEB transcription factors in extravillous trophoblasts, facilitating deep trophoblast invasion in humans. Our data suggest that ZNF554 downregulation by epigenetic mechanisms is involved in preeclampsia pathology.
Funding: This research was supported by the Hungarian Academy of Sciences Momentum “LP2014-7/2014 (T. N. G.) and Premium_2019-436 (B. A.) grants; the Hungarian National Research, Development and Innovation Fund grant “FIEK_16-1-2016-0005”.