Mutant p53 regulates enhancer-associated H3K4 monomethylation through interactions with the methyltransferase MLL4

Abstract

Monomethylation of histone H3 lysine 4 (H3K4me1) is enriched at enhancers that are primed for activation and the levels of this histone mark are frequently altered in various human cancers. Yet, how alterations in H3K4me1 are established and the consequences of these epigenetic changes in tumorigenesis are not well understood. Using ChIP-Seq in human colon cancer cells, we demonstrate that mutant p53 depletion results in decreased H3K4me1 levels at active enhancers that reveal a striking colocalization of mutant p53 and the H3K4 monomethyltransferase MLL4 following chronic tumor necrosis factor alpha (TNFα) signaling. We further reveal that mutant p53 forms physiological associations and direct interactions with MLL4 and promotes the enhancer binding of MLL4, which is required for TNFα-inducible H3K4me1 and histone H3 lysine 27 acetylation (H3K27ac) levels, enhancer-derived transcript (eRNA) synthesis, and mutant p53-dependent target gene activation. Complementary studies with recombinant chromatin and purified proteins demonstrate that binding of the MLL3/4 complex and H3K4me1 deposition is enhanced by mutant p53 and p300-mediated acetylation, which in turn reflects a MLL3/4-dependent enhancement of mutant p53 and p300-dependent transcriptional activation. Collectively, our findings establish a mechanism in which mutant p53 cooperates with MLL4 to regulate aberrant enhancer activity and tumor-promoting gene expression in response to chronic immune signaling.

Gain-of-function mutant p53 in cancer progression and therapy

“…Mutp53 also binds to several chromatin regulatory genes to upregulate their expression, including histone lysine methyltransferase genes MLL1 and MLL2 and histone lysine acetyltransferase gene MOZ, which in turn results in genome-wide increases of histone methylation and acetylation to regulate gene expression ( Zhu et al., 2015 ). Furthermore, mutp53 can regulate genome-wide gene expression through directly interacting with the histone lysine methyltransferase protein MLL4 ( Rahnamoun et al., 2018 ) or inducing chromatin remodeling via the interaction with the SWI/SNF chromatin-remodeling complex ( Pfister et al., 2015 ) and Pontin, the AAA+ ATPase that is associated with several chromatin-remodeling complexes (e.g. Ino80, TIP60/NuA4, and SWR1 complexes) and involved in chromatin remodeling ( Zhao et al., 2015 ).…”

GR and LSD1/KDM1A-Targeted Gene Activation Requires Selective H3K4me2 Demethylation at Enhancers

“…H3K4me2 is necessary for genomic localization of FoxA1, a pioneer factor for the androgen receptor (AR) and the estrogen receptor (ER) (Lupien et al, 2008) and, is a distinguishing epigenetic mark at cell-type-specific enhancers (Pekowska et al, 2010;Wang et al, 2014). However, recent studies challenge the canonical view of H3K4 methylation at enhancers by showing that enhancer methylation mediated by MLL3 and MLL4 is dispensable for gene regulation and development (Dhar et al, 2018;Jang et al, 2019;Rahnamoun et al, 2018). Thus, the role of different H3K4-methyl states and their regulation at enhancers is complex and remains poorly understood.…”

Potential molecular mechanism of ACE gene at different time points in STEMI patients based on genome-wide microarray dataset

“…In addition, 10 hub genes were identified using CytoHubba with a high level of connectivity - TP53 ( p53 ), KMT2B ( MLL4 ), KMT2D, EP400 ( p400 ), HDAC7, RAB2A, PIK3CD ( PI3K ), MED12 ( OPA1 ), HUWE1, and RHEB ( mTORC1 ). In the context of cellular immunity and apoptosis, Rahnamoun et al [49] reported a novel mechanism in which the mutant TP53 and KMT2B cooperated to regulate aberrant enhancer activity and tumor-promoting gene expression in response to chronic immune signaling. The EP400 E1A-associated protein, which mediates H2A.Z incorporation at specific promoters, plays a major role in cell fate decisions; it promotes cell cycle progression and inhibits apoptosis or senescence [50].…”