A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription

Abstract

SUMMARY Enhancer activation is a critical step for gene activation. Here we report an epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of inactive enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an “active enhancer landscape” and defines a detailed mechanism for the joint deposition of H3K4me1 and H3K27ac.

Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality

“…We next investigated gene expression alterations induced by KDM6A knockout to clarify molecular mechanisms underlying malignant features of the KDM6A‐negative PDAC. Since KDM6A decreases repressive histone mark H3K27me3 and increases active histone mark H3K27ac to upregulate the expression levels of target genes, 22 genes (Fig. a and Supporting Information Table S7) and 19 gene sets (Fig.…”

“…As Wang et al . have described cooperative regulation of H3K27 acetylation in mammalian cells by a histone acetyltransferase p300 and the COMPASS‐like complex including histone modifying components KDM6A and MLL4, KDM6A and p300 were co‐localized at the promoter region of CDKN1A , where H3K27ac was enriched, in the KDM6A‐OE KLM1 cells by using qChIP‐PCR. Co‐immunoprecipitation assays also showed protein–protein interaction between them in the KLM1 cells transiently transfected with vectors for ectopic expression of FLAG‐tagged KDM6A and p300 (Fig.…”

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

“…These systematic analyses suggest three major groups of proteins interacting with UTX. 23 The second group of interacting proteins consists of DNA-binding transcription factors, especially nuclear receptors such as estrogen receptors, 5 retinoic acid receptors 24 and peroxisome proliferator-activated receptors. It comprises MLL2, MLL3, ASH2L, RBBP5, WDR5, NCOA6 (also known as AIB3), DPY30, PAXIP (also known as PTIP) and coordinates several biochemical processes associated with gene transcriptional activation, especially H3K4 methylation and H3K27me2/me3 demethylation.…”

Histone Marks in the ‘Driver’s Seat’: Functional Roles in Steering the Transcription Cycle

“…Together with H3K4me1, H3K27ac often denotes active enhancers, and these two modifications have clear interplay with one another. The writers of H3K4me1, MLL3 and MLL4, interact with the writers of H3K27ac, p300 and CBP, and are required for the binding of these HATs to chromatin [103,104]. This suggests that H3K4me1 may precede H3K27ac in a step-wise fashion, and the Roeder lab additionally showed that the presence of the MLL4 complex stimulates p300-mediated H3K27ac in a cell-free system.…”

“…This suggests that H3K4me1 may precede H3K27ac in a step-wise fashion, and the Roeder lab additionally showed that the presence of the MLL4 complex stimulates p300-mediated H3K27ac in a cell-free system. However, the ability of MLL4 to write H3K4me1 was also dependent on the presence of p300 and acetyl-CoA [104], suggesting that the interplay between H3K4me1 and H3K27ac may be more complex than previously thought.…”