H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas
H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas
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DOI：
10.1038/s41388-019-0808-4
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发表时间：
2019-07-04
期刊：
影响因子：
8
通讯作者：
Huang, Yingqun
中科院分区：
文献类型：
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作者：
Cao, Tiefeng;Jiang, Ying;Huang, Yingqun
子宫肌瘤或子宫肌瘤(UF)是以平滑肌细胞增生和细胞外基质(ECM)过度沉积为特征的良性肿瘤。与80%的女性相似，25%的女性有症状，UF带来巨大的痛苦，在全球范围内是一种经济负担；它们会导致剧烈的疼痛和出血，是子宫切除术的主要原因。然而，UF的研究严重不足，可用的有效治疗方案很少；那些经常可用的UF会产生显著的副作用，如更年期症状。最近，基因组规模的综合研究揭示了关键驱动基因的突变和肌瘤亚型特异性表达的变化，MED12和HMGA2共同贡献了近90%的UF，但它们对表达的调控尚不清楚。在此，我们报告了H19长非编码RNA(LncRNA)在UF中的表达异常增加。利用细胞培养、全基因组转录组和甲基化图谱分析，我们证明H19通过多种机制促进MED12、HMGA2和关键的ECM重塑基因的表达，其中包括TET3的一种新的表观遗传修饰。我们的结果标志着进化上保守的lncRNA在UF的发病机制和Tet表达调控中的第一个例子。鉴于H19单核苷酸多态(SNP)与UF风险增加和肿瘤大小之间的联系，以及由H19调控的关键通路基因驱动的多种肌瘤亚型的存在，我们提出了H19介导的子宫肌瘤发病的统一机制，并为未来探索子宫肌瘤的新靶向治疗提供了一条途径。
Uterine leiomyomas or fibroids (UFs) are benign tumors characterized by hyperplastic smooth muscle cells and excessive deposition of extracellular matrix (ECM). Afflicting similar to 80% of women, and symptomatic in 25%, UFs bring tremendous suffering and are an economic burden worldwide; they cause severe pain and bleeding, and are the leading cause of hysterectomy. Yet, UFs are severely understudied with few effective treatment options available; those that are available frequently have significant side effects such as menopausal symptoms. Recently, integrated genome-scale studies have revealed mutations and fibroid subtype-specific expression changes in key driver genes, with MED12 and HMGA2 together contributing to nearly 90% of all UFs, but their regulation of expression is poorly characterized. Here we report that the expression of H19 long noncoding RNA (lncRNA) is aberrantly increased in UFs. Using cell culture and genome-wide transcriptome and methylation profiling analyses, we demonstrate that H19 promotes expression of MED12, HMGA2, and key ECM-remodeling genes via multiple mechanisms including a new class of epigenetic modification by TET3. Our results mark the first example of an evolutionarily conserved lncRNA in pathogenesis of UFs and regulation of TET expression. Given the link between a H19 single-nucleotide polymorphism (SNP) and increased risk and tumor size of UFs, and the existence of multiple fibroid subtypes driven by key pathway genes regulated by H19, we propose a unifying mechanism for pathogenesis of uterine fibroids mediated by H19 and identify a pathway for future exploration of novel target therapies for uterine leiomyomas.