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H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas.

Oncogene (2019-05-16)
Tiefeng Cao, Ying Jiang, Zhangsheng Wang, Na Zhang, Ayman Al-Hendy, Ramanaiah Mamillapalli, Amanda N Kallen, Pinar Kodaman, Hugh S Taylor, Da Li, Yingqun Huang
ABSTRACT

Uterine leiomyomas or fibroids (UFs) are benign tumors characterized by hyperplastic smooth muscle cells and excessive deposition of extracellular matrix (ECM). Afflicting ~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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-TET3, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Progesterone, ≥99%
Sigma-Aldrich
β-Estradiol, ≥98%
Sigma-Aldrich
Minimum Essential Medium Eagle, with Earle′s salts and non-essential amino acids, without L-glutamine, phenol red and sodium bicarbonate, Modified, powder, suitable for cell culture