Identification of HTRA4 as a Transcriptional Target of p63 in Trophoblast

IF 4.7 2区 医学 Q1 PATHOLOGY
Mary E. Donohoe , Robert Morey , Yingchun Li , Donald Pizzo , Sampada Kallol , Hee-Young Cho , Francesca Soncin , Mana M. Parast
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引用次数: 0

Abstract

The placenta plays a crucial role in pregnancy success. ΔNp63α (p63), a transcription factor from the TP53 family, is highly expressed in villous cytotrophoblasts (CTBs), the epithelial stem cells of the human placenta, and is involved in CTB maintenance and differentiation. We examined the mechanisms of action of p63 by identifying its downstream targets. Gene expression changes were evaluated following overexpression and knockdown of p63 in the JEG3 choriocarcinoma cell line, using microarray-based RNA profiling. High-temperature requirement A4 (HTRA4), a placenta-specific serine protease involved in trophoblast differentiation and altered in preeclampsia, was identified as a gene reciprocally regulated by p63, and its expression was characterized in primary human placental tissues by RNA-sequencing and in situ hybridization. Potential p63 DNA-binding motifs were identified in the HTRA4 promoter, and p63 occupancy at some of these sites was confirmed using chromatin immunoprecipitation, followed by quantitative PCR in both JEG3 and trophoblast stem cells. These data begin to identify members of the transcriptional network downstream of p63, thus laying the groundwork for probing mechanisms by which this important transcription factor regulates trophoblast stemness and differentiation.

确定 HTRA4 是滋养层母细胞中 p63 的转录靶标
胎盘在妊娠成功与否中起着至关重要的作用。TP53家族的转录因子ΔNp63α(p63)在绒毛细胞滋养母细胞(CTB)(人类胎盘的上皮干细胞)中高度表达,并参与CTB的维持和分化。我们通过确定 p63 的下游靶点来研究其作用机制。使用基于芯片的 RNA 图谱分析评估了 JEG3 绒毛膜癌细胞系中过表达和敲除 p63 后的基因表达变化。高温要求 A4(HTRA4)是一种胎盘特异性丝氨酸蛋白酶,参与滋养层细胞分化并在子痫前期发生改变。在 HTRA4 启动子中发现了潜在的 p63 DNA 结合基团,并通过染色质免疫共沉淀和定量 PCR 在 JEG3 和滋养层干细胞中证实了 p63 在其中一些位点的占据。这些数据开始确定p63下游转录网络的成员,从而为探究这一重要转录因子调控滋养细胞干性和分化的机制奠定了基础。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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