A Long Noncoding RNA, lncRNA-Amhr2, Plays a Role in Amhr2 Gene Activation in Mouse Ovarian Granulosa Cells

Abstract

Anti-Müllerian hormone (AMH) is critical to the regression of Müllerian ducts during mammalian male differentiation and targets ovarian granulosa cells and testicular Sertoli and Leydig cells of adults. Specific effects of AMH are exerted via its receptor, AMH type II receptor (Amhr2), but the mechanism by which the Amhr2 gene is specifically activated is not fully understood. To see whether a proximal promoter was sufficient for Amhr2 gene activation, we generated transgenic mice that bore the enhanced green fluorescent protein (EGFP) gene driven by a 500-bp mouse Amhr2 gene promoter. None of the established 10 lines, however, showed appropriate EGFP expression, indicating that the 500-bp promoter was insufficient for Amhr2 gene activation. As a regulatory element, we found a long noncoding RNA, lncRNA-Amhr2, transcribed from upstream of the Amhr2 gene in ovarian granulosa cells and testicular Sertoli cells. In primary granulosa cells, knockdown of lncRNA-Amhr2 resulted in a decrease of Amhr2 messnger RNA level, and a transient reporter gene assay showed that lncRNA-Amhr2 activation increased Amhr2 promoter activity. The activity was correlated with lncRNA-Amhr2 transcription in stably transfected OV3121 cells derived from mouse granulosa cells. Moreover, by the Tet-on system, the induction of lncRNA-Amhr2 transcription dramatically increased Amhr2 promoter activity in OV3121 cells. These results indicate that lncRNA-Amhr2 plays a role in Amhr2 gene activation in ovarian granulosa cells by enhancing promoter activity, providing insight into Amhr2 gene regulation underlying the AMH signaling in the female reproductive system.

Epigenetic Reprogramming During Somatic Cell Nuclear Transfer: Recent Progress and Future Directions

“…During DNA methylation reprogramming, lncRNAs can interact with enzymes related to DNA methylation or demethylation (Dnmts and Tets), and determine DNA methylation reconstruction to regulate gene expression. When a gene needs to be activated, lncRNAs recruit DNA demethylationrelated enzymes, such as Tets, to the gene promoter and help to achieve gene DNA demethylation, and when a gene needs to be silenced, lncRNAs interact with Dnmts to establish and maintain DNA methylation of a gene promoter Hamazaki et al, 2015;Wang et al, 2015;Zhou et al, 2015;Kimura et al, 2017). Therefore, lncRNAs can interact with the DNA methylation reprogramming-related enzymes to regulate DNA methylation reprogramming and regulate gene expression.…”

Lnc-GULP1-2:1 Affects Granulosa Cell Proliferation by Regulating COL3A1 Expression and Localization​

“…LncRNAs are involved in a variety of biological functions and pathological processes, including proliferation, differentiation, development, apoptosis and carcinogenesis [7][8][9]. For example, overexpression of lncRNA-Amhr2 in mouse granulosa cells resulted in decreased mRNA levels of Amhr2, and activation of lncRNA-Amhr2 increases Amhr2 promoter activity [8]. Furthermore, the expression of lncRNA and its regulation of downstream target genes have higher tissue and organ speci city.…”

LncRNA Gm2044 promotes 17β‐estradiol synthesis in mpGCs by acting as miR‐138‐5p sponge

“…For example, lncRNA HOTAIR can promote the proliferation of primordial follicular granulosa cells by strengthening the PI3K/Akt‐p27/Cyclin D signaling pathway and blocking the negative regulatory factor Pten from this pathway, thus accelerating the growth of primordial follicles (Adhikari, Risal, Liu, & Shen, ). LncRNA‐Amhr2 promotes the activity of the Amhr2 gene promoter in primary follicular granulosa cells, enhances the expression of the Amhr2 gene, regulates the signaling pathway of anti‐Mullerian hormone and then affects the development of primary follicles (Kimura, Yoneda, Kurihara, Mayama, & Matsubara, ). The lncRNA Neat1 is mainly expressed in the corpus luteum stage during follicular development, and knock‐out mice have luteinization disorder, low progesterone levels in the blood, and significantly abnormal follicular development, leading to infertility in about half of the mice (Nakagawa et al, ).…”

“…For example, lncRNA HOTAIR can promote the proliferation of primordial follicular granulosa cells by strengthening the PI3K/Akt-p27/Cyclin D signaling pathway and blocking the negative regulatory factor Pten from this pathway, thus accelerating the growth of primordial follicles (Adhikari, Risal, Liu, & Shen, 2013). LncRNA-Amhr2 promotes the activity of the Amhr2 gene promoter in primary follicular granulosa cells, enhances the expression of the Amhr2 gene, regulates the signaling pathway of anti-Mullerian hormone and then affects the development of primary follicles (Kimura, Yoneda, Kurihara, Mayama, & Matsubara, 2017).…”