Intrachromosomal Looping and Histone K27 Methylation Coordinately Regulates the lncRNA <i>H19</i>-Fetal Mitogen <i>IGF2</i> Imprinting Cluster in the Decidual Microenvironment of Early Pregnancy
Xue Wen,
Qi Zhang,
Lei Zhou,
Zhaozhi Li,
Xue Wei,
Wang Yang,
Jiaomei Zhang,
Hui Li,
Zijun Xu,
Xueling Cui,
Songling Zhang,
Yufeng Wang,
Wei Li,
Andrew R. Hoffman,
Zhonghui Liu,
Ji-Fan Hu,
Jiuwei Cui
Affiliations
Xue Wen
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Qi Zhang
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Lei Zhou
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Zhaozhi Li
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Xue Wei
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Wang Yang
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Jiaomei Zhang
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Hui Li
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Zijun Xu
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Xueling Cui
Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
Songling Zhang
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Yufeng Wang
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Wei Li
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Andrew R. Hoffman
Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA
Zhonghui Liu
Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
Ji-Fan Hu
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Jiuwei Cui
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun 130061, China
Recurrent spontaneous abortion (RSA) is a highly heterogeneous complication of pregnancy with the underlying mechanisms remaining uncharacterized. Dysregulated decidualization is a critical contributor to the phenotypic alterations related to pregnancy complications. To understand the molecular factors underlying RSA, we explored the role of longnoncoding RNAs (lncRNAs) in the decidual microenvironment where the crosstalk at the fetal–maternal interface occurs. By exploring RNA-seq data from RSA patients, we identified H19, a noncoding RNA that exhibits maternal monoallelic expression, as one of the most upregulated lncRNAs associated with RSA. The paternally expressed fetal mitogen IGF2, which is reciprocally coregulated with H19 within the same imprinting cluster, was also upregulated. Notably, both genes underwent loss of imprinting, as H19 and IGF2 were actively transcribed from both parental alleles in some decidual tissues. This loss of imprinting in decidual tissues was associated with the loss of the H3K27m3 repressive histone marker in the IGF2 promoter, CpG hypomethylation at the central CTCF binding site in the imprinting control center (ICR), and the loss of CTCF-mediated intrachromosomal looping. These data suggest that dysregulation of the H19/IGF2 imprinting pathway may be an important epigenetic factor in the decidual microenvironment related to poor decidualization.
