1. Enhancer Malfunction in Cancer
Hans-Martin Herz, Deqing Hu, Ali Shilatifard 
Molecular Cell 
Volume 53, Issue 6, Pages (March 2014)
DOI: /j.molcel
Copyright © 2014 Elsevier Inc. Terms and Conditions

2. Figure 1
A Model for Transcriptional Activation by cis-Regulatory Elements
(A) Metazoan cis-regulatory elements also called “enhancers” can activate gene expression over more than hundreds of kilobases but can also function over very short distances. Enhancers contain binding sites for activating or repressing transcription factors (TFs) that are often recruited in response to environmental or developmental signals.
(B) TFs often recruit chromatin-modifying coactivators or corepressors. Coactivators such as CBP/p300 and MLL3/MLL4 have been demonstrated to acetylate histone H3 on lysine 27 (H3K27ac, highlighted in pink) or monomethylate histone 3 on lysine 4 (H3K4me1, highlighted in green) around enhancers, respectively.
(C) A looping mechanism mediated by factors such as cohesin and the Mediator complex can bring enhancers into close proximity to promoters. Long-range interactions between enhancers and promoters have been shown to be stabilized by members of the cohesin complex, and the Mediator complex supports the interaction of enhancer-bound transcription factors and coactivators such as MLL3/MLL4 and CBP/p300 with the basal transcription machinery on promoters.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2014 Elsevier Inc. Terms and Conditions

3. Figure 2 Trr/MLL3/MLL4 COMPASS-like Complex-Dependent Enhancers
Coverage profiles arranged for enrichment of H3K4 monomethylation (H3K4me1) at promoter-distal sites (>1 kb) in the human colorectal carcinoma cell line, HCT116 (MLL3Δset, column 1), or HCT116 cells with a MLL4 deletion (MLL3Δset/4Δset, column 2). Sites are arranged in a vertical gradient with a higher enrichment of H3K4 monomethylation at the top and lower levels of H3K4me1 toward the bottom. A large percentage (∼70%) of putative enhancers exhibits a significant loss in H3K4 monomethylation (p < 1e−3) in the absence of both MLL3 and MLL4 (compare column 2 with column 1 in first panel), while a minority of putative enhancers (∼30%) is independent of MLL3/MLL4 for their H3K4me1 status (we call these enhancers Trr/MLL3/MLL4-independent enhancers; compare column 2 with column 1 in second panel). Data for this figure were adopted from Hu et al. (2013) with permission from the American Society for Microbiology.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2014 Elsevier Inc. Terms and Conditions

4. Figure 3
Misregulation of MLL3/MLL4-Dependent Enhancer Function in Cancer Pathogenesis
Two models proposing how MLL3/MLL4 mutations can either result in inappropriate enhancer-mediated inactivation of tumor suppressor genes or activation of oncogenes are described here. In (A), MLL3/MLL4 loss-of-function scenario on the enhancer of a tumor suppressor gene is shown. MLL3/MLL4 mutations could either result in a destabilization of MLL3/MLL4, reduced association of MLL3/MLL4 with recruiting TFs on enhancers, or catalytic inactivation of MLL3/MLL4. In any case, the outcome would be diminished or eliminated enhancer activation of tumor suppressor genes. In (B), MLL3/MLL4 gain-of-function scenario on the enhancer of oncogenes is shown. MLL3/MLL4 mutations could either result in increased MLL3/MLL4 stability, increased affinity of MLL3/MLL4 toward MLL3/MLL4-recruiting TFs, or catalytic hyperactivation of MLL3/MLL4 on enhancers regulating the expression of oncogenes.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2014 Elsevier Inc. Terms and Conditions