Abstract
A number of genome-wide analyses have revealed that estrogen receptor Ī± binding to and regulation of its target genes correlate with binding of FOXA1, a pioneer factor, to nearby DNA sites in MCF-7 breast cancer cells. The enhancer element-specific histone H3K4me1/2 mark is enriched at the specific FOXA1/ERĪ± recruitment sites in chromatin, but the mechanism by which these enhancer marks are established in chromatin before hormone treatment is unclear. Here, we show that mixed-lineage leukemia 1 (MLL1) protein is a key determinant that maintains permissive chromatin structure of the TFF1 enhancer region. MLL1 occupies the TFF1 enhancer region and methylates H3K4 before hormone stimulation. In vitro, MLL1 binds directly to the CpG-rich region of the TFF1 enhancer, and its binding is dependent on hypomethylation of DNA. Furthermore, the depletion of MLL1 in MCF-7 cells results in a dramatic decrease of chromatin accessibility and recruitment of FOXA1 and ERĪ± to the enhancer element. Our study defines the mechanism by which MLL1 nucleates histone H3K4 methylation marks in CpG-enriched regions to maintain permissive chromatin architecture and allow FOXA1 and estrogen receptor Ī± binding to transcriptional regulatory sites in breast cancer cells.
Highlights
Enhancers are distal cis-acting elements that regulate gene expression in a highly controlled manner
Compared with cells transfected with non-specific siRNA, the estradiol (E2)-induced expression of TFF1, GREB1, PgR, SGK3 and PKIB was compromised (Figure 1A) when mixed-lineage leukemia 1 (MLL1) was depleted from MCF-7 cells by siRNA duplexes (Figure 1B and Supplementary Figure S1B)
The levels of E2-induced MYC and CXCL12 mRNAs were marginally reduced, and the basal expression of CCND1 was affected by the depletion of MLL1, and MLL1 is critically required for E2-induced expression of most of the ERa target genes examined in this study
Summary
Enhancers are distal cis-acting elements that regulate gene expression in a highly controlled manner. It is generally thought that the enhancer region is looped out or organized to permit enhancerāpromoter interaction. This flexibility of enhancer element position relative to the transcription start site, impedes the comprehensive assignment of enhancer elements to the target genes they control. Recent genome-wide studies from independent laboratories have revealed several characteristic chromatin āsignaturesā that define the enhancer elements in genes. A recent study of embryonic stem cells suggested three classes of enhancers: active (H3K4me1+, H3K27ac+), intermediate (H3K4me1+, H3K27Ć) and poised (H3K4me1+, H3K27me3+) [4,5]. The mechanisms by which these histone marks are maintained and cooperate with other epigenetic factors, such as DNA methylation and pioneer factors, remain unclear
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