Histone Methylases MLL1 and MLL3 Coordinate with Estrogen Receptors in Estrogen-Mediated HOXB9 Expression

Abstract

Homeobox gene HOXB9 is a critical player in development of mammary gland and sternum and in regulation of Renin which is closely linked with blood pressure control. Our studies demonstrated that HOXB9 gene is transcriptionally regulated by estrogen (E2). HOXB9 promoter contains several estrogen-response elements (ERE). Reporter assay based experiments demonstrated that HOXB9 promoter EREs are estrogen-responsive. Estrogen receptors ERα and ERβ are essential for E2-mediated transcriptional activation of HOXB9. Chromatin immuno-precipitation assay demonstrated that ERs bind to HOXB9 EREs as a function of E2. Similarly, histone methylases MLL1 and MLL3 also bind to HOXB9 EREs and play critical role in E2-mediated transcriptional activation of HOXB9. Overall, our studies demonstrated that HOXB9 is an E2-responsive gene and ERs coordinate with MLL1 and MLL3 in E2-mediated transcriptional regulation of HOXB9.

Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer

“…(60, 64, 65). Studies demonstrate that mixed lineage leukemia (MLL) family of histone methylases act as ER-coregulators during E2-mediated gene activation (14, 15, 44, 48, 49, 64–74). Herein, we examined, if ER and MLLs are involved in the E2 and BPA induced HOXC6 expression in MCF7 cells.…”

“…The qPCR results were analyzed using the CFX manager software. The experiments were repeated at least thrice with three replicates each time (16, 46–48). …”

“…Control transfections were done using empty pGL3 promoter vector without any ERE insertion. At 30 h post-transfection, cells were treated with 1 nM E2 or 10 nM BPA and incubated for an additional 8 h. Total protein was extracted and then subjected to luciferase assay using Dual-Glo Luciferase Assay System (Promega) as instructed and detected using a microplate reader (Flowstar-Omega) (14, 15, 41, 44, 48–50). Each treatment was done in four replicates and the experiment was repeated at least twice.…”

Hormonal and non-hormonal bases of maternal behavior: The role of experience and epigenetic mechanisms

“…For example, the p160 coactivator protein SRC1 recruits CREB binding protein (CBP), p300, and CBP/p300 associated factor (PCAF), which engage in HAT activity (Sheppard et al, 2003). p160 coactivators also recruit histone methyltransferase enzymes such as CARM1, MLL1, and MLL3, which methylate histone protein tails and facilitate the transcription of ER-induced genes (Ansari et al, 2011;Teyssier et al, 2002). Histone methylation can have activating or repressive effects on gene expression through the recruitment of additional proteins that regulate transcription (Wozniak and Strahl, 2014).…”

The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role in Clinical Dilated Cardiomyopathy

“…In mammals, there are at least nine H3K4-specific histone methyltransferases (HMTs), including mixed lineage leukemia (MLL) families consisting of MLL, MLL2, MLL3, MLL4, MLL5, SETD1A and SETD1B (6)(7)(8). The MLL family members, each possessing the highly conserved suppressor of variegation, enhancer of zeste, trithorax (SET) domain responsible for HMT activity, exist as distinct multiprotein complexes (namely complex of proteins associated with Set1, or COMPASS) with several common subunits, including Ash2, Wdr5, Rbbp5 and Dpy30 (9,10).…”