期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 25, 期 -, 页码 251-263出版社
CELL PRESS
DOI: 10.1016/j.omtn.2021.05.006
关键词
-
资金
- Qing Lan Project of Jiangsu Province
- National Natural Science Foundation of China [31772568]
This study identified BRE-AS as a crucial AS-lncRNA involved in granulosa cell apoptosis, potentially contributing to the initiation of follicular atresia. Through direct interaction with the pre-mRNA transcript of its overlapping gene BRE, BRE-AS induces granulosa cell apoptosis.
Antisense long noncoding RNAs (AS-lncRNAs), a sub-class of lncRNAs, are transcribed in the opposite direction from their overlapping protein-coding genes and are implicated in various physiological and pathological processes. However, their role in female reproduction remains largely unknown. Here, we report that BRE-AS, an AS-lncRNA transcript from intron 10 of the protein-coding gene BRE, is involved in granulosa cell (GC) apoptosis. Based on our previous RNA sequencing data, we identified 28 AS-lncRNAs as important in the initiation of porcine follicular atresia, with BRE-AS showing the most significant upregulation in early atretic follicles. In this study, gain- and loss-of-function assays demonstrated that BRE-AS induces early apoptosis in GCs. Mechanistically, BRE-AS acts in cis to suppress the expression of BRE, an anti-apoptotic factor, via direct interaction with the pre-mRNA transcript of the latter, inducing increased GC apoptosis. Notably, we also found that BRE-AS was upregulated in SMAD4-silenced GCs. SMAD4 was identified as a transcriptional repressor of BRE-AS because it inhibits BRE-AS expression and BRE-AS-mediated GC apoptosis. In conclusion, we not only identified a novel AS-IncRNA related to the early apoptosis of GCs and initiation of follicular atresia but also described a novel regulatory pathway, SMAD4/BRE-AS/BRE, coordinating GC function and female fertility.
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