Dataset Information

Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

ABSTRACT: Transcriptional enhancers instruct spatiotemporal gene expression and their dysfunction has long been known as one of the primary mechanisms that drive tumorigenesis and confer malignant tumor cell behaviors. However, it is largely unknown about whether tumor cell enhancer regulation plays a role in tumor immune evasion and anti-tumor immune response. Here, we demonstrate that tumor cell deletion of Mll3 and Mll4, two members of COMPASS family for enhancer H3K4 mono-methylation, increases tumor cell immunogenicity and promotes anti-tumor immune response. Loss of Mll4 potentiates therapeutic response to anti-Pd1 blockade in the murine melanoma model. Mechanistically, Mll4 loss leads to the widespread decrease of epigenetic signatures at both typical and super-enhancers, including the super-enhancer for Ago2 subunit of RNA-induced silencing complex (RISC) and the enhancers for DNA methyltransferases Dnmt3a and Dnmt1. Downregulation of Ago2 expression leads to double-stranded RNA (dsRNAs) stress to elicit interferon response while decreased expression of Dnmt3a and Dnmt1 derepresses Gsdmd and inflammatory caspases to trigger Gsdmd-mediated pyroptosis in Mll4-deficient tumor cells. Notably, transcriptional induction of interferon signaling and Gsdmd-mediated tumor cell pyroptotic death is crucial for the increased anti-tumor immunity and the improved immunotherapeutic efficacy in Mll4-deficient tumors. These findings reveal an important immune regulatory role of tumor cell enhancer regulation and provide molecular insights into the immunotherapeutic vulnerabilities of tumors bearing MLL3/MLL4 deficiency or loss of function mutations.

ORGANISM(S): Mus musculus

PROVIDER: GSE192714 | GEO | 2022/10/05

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:FOXA1 is a pioneer factor that is important in hormone dependent cancer cells to stabilise nuclear receptors, such as estrogen receptor (ER) to chromatin. FOXA1 binds to enhancers regions that are enriched in H3K4mono- and dimethylation (H3K4me1, H3K4me2) histone marks and evidence suggests that these marks are requisite events for FOXA1 to associate with enhancers to initate subsequent gene expression events. However, exogenous expression of FOXA1 has been shown to induce H3K4me1 and H3K4me2 signal at enhancer elements and the order of events and the functional importance of these events is not clear. We performed a FOXA1 Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells in order to identify FOXA1 interacting partners and we found histone-lysine N-methyltransferase (MLL3) as the top FOXA1 interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition, in line with our observation that MLL3 associates with an enhancer specific protein. We performed MLL3 ChIP-seq in breast cancer cells and unexpectedly found that MLL3 binds mostly at non-promoter regions enhancers, in contrast to the prevailing hypothesis. MLL3 was shown to occupy regions marked by FOXA1 occupancy and as expected, H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. Motif analysis and subsequent genomic mapping revealed a role for Grainy head like protein-2 (GRHL2) which was shown to co-occupy regions of the chromatin with MLL3. Regions occupied by all three factors, namely FOXA1, MLL3 and GRHL2, were most enriched in H3K4me1. MLL3 silencing decreased H3K4me1 at enhancer elements, but had no appreciable impact on H3K4me3 at enhancer elements. We identify a complex relationship between FOXA1, MLL3 and H3K4me1 at enhancers in breast cancer and propose a mechanism whereby the pioneer factor FOXA1 can interact with a chromatin modifier MLL3, recruiting it to chromatin to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.

Dataset Information

Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets