2015 Study Abstract
Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo.
It is important to note that, HOTAIR is an antisense transcript and lncRNA. Therefore, our studies also demonstrate that endocrine disruptors can disrupt the noncoding RNAs and can induce antisense transcripts, in a similar fashion as protein coding genes from the sense strands. Our studies revealed novel epigenetic mechanism of endocrine disruption, novel roles of MLL histone methylases and their coordination with ERs and various ER-coregulators during endocrine disruption, both in vitro and in vivo. Although further in vivo analyses are required to understand the detailed mechanism of HOTAIR gene expression and misregulation by EDCs, synthetics estrogens, and other environmental toxins/chemical, our observations indicate that exposure to BPA or DES may turn on the expression of HOTAIR in vivo, in a very similar fashion to estrogen even in the absence of estrogen, and that may result in adverse health effects including cancer and other hormonally regulated disorders.
Sources and more information
- Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo, J Steroid Biochem Mol Biol. NCBI PMID: 24533973, 2014 May;141:160-70. doi: 10.1016/j.jsbmb.2014.02.002. Epub 2014 Feb 14.
- Full text NIHMSID: NIHMS569531, PMCID: PMC4025971, 2015 May 1.
DES DiEthylStilbestrol Resources
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