A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition

Soto‐Feliciano, Yadira M.; Sánchez‐Rivera, Francisco J.; Perner, Florian; Barrows, Douglas; Kastenhuber, Edward R.; Ho, Yu-Jui; Carroll, Thomas; Xiong, Yijun; Anand, Disha; Soshnev, Alexey A.; Gates, Leah; Beytagh, Mary C.; Cheon, David; Gu, Shengqing; Liu, X. Shirley; Krivtsov, Andrei V.; Meneses, Maximiliano; Stanchina, Elisa de; Stone, Richard; Armstrong, Scott A.; Lowe, Scott W.; Allis, C. David

doi:10.1101/2021.10.22.465184

Cited by 4 publications

(7 citation statements)

References 133 publications

(314 reference statements)

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“…Interestingly, Mll3 suppression preferentially limited the MLL3/4 enrichment at promoters and shifted residual complex binding towards intergenic regions. Such dynamic regulation of distinct cis-acting elements by the MLL3/4 complex has also been observed in other contexts (Cheng et al, 2014; Soto-Feliciano et al, 2021), where the non-canonical binding of MLL3/4 at promoters is a recurrent tumor suppressive mechanism in cancer cells. Further studies into the action and regulation of MLL3/4 complexes at promoters will be informative and may shed new insights into the actions of the COMPASS-like complex in cancer.…”

Section: Discussionsupporting

confidence: 59%

“…It is noteworthy that the COMPASS-like complexes are biochemically and functionally similar to Trithorax complexes in Drosophila , which have an evolutionarily conserved antagonistic relationship with Polycomb Repressive Complexes (PRC1 and PRC2) that controls epigenetic memory and cell fate during development (Mills, 2010; Piunti and Shilatifard, 2016). Our findings suggest such antagonism extends to tumor suppression in mammalian cells, likely via regulation of Cdkn2a and other tumor suppressor genes (Soto-Feliciano et al, 2021).…”

Section: Discussionmentioning

confidence: 65%

“…MLL3 and MLL4 are histone methyltransferases that can deposit the H3K4 mono-methylation mark at genomic enhancers and intergenic regions during organ development (Hu et al, 2013). However, more recent studies indicate that MLL3 and MLL4 are also capable of binding to promoter regions (Cheng et al, 2014; Dhar et al, 2016; Wang et al, 2010), especially in the context of cancer (Soto-Feliciano et al, 2021). To determine the genomic binding patterns of MLL3 in HCC, we performed MLL3 ChIP-sequencing (ChIP-Seq) analysis in Myc ; sgMll3 (sgMll3.1 which generates heterozygous or homozygous indels) and Myc ; sgp53 liver cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

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MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

Soto‐Feliciano

Zhu

Huang

et al. 2022

Preprint

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Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3/KMT2C) histone methyltransferase occur in a range of solid tumors and heterozygous deletions encompassing MLL3 occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Mll3 cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded genes, Ink4a and Arf. Conversely, elevated MLL3 expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Mll3 restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in MLL3 and CDKN2A display mutual exclusivity in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

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MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

Soto‐Feliciano

Zhu

Huang

et al. 2022

Preprint

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“…The following sgRNA plasmids were used in this manuscript: LRT2B (Addgene, #110854) ( ref. 1 ), pUSEPR ( U 6- s gRNA- E FS- P uro-P2A-Turbo R FP) 2 , and pUSEBR (pUSE- B last-P2A-Turbo R FP) (this manuscript). We cloned Esp3I/BsmBI-compatible annealed and phosphorylated oligos encoding sgRNAs into Esp3I/BsmBI-linearized pLRT2B, pUSEPR, or pUSEBR using high concentration T4 DNA ligase (NEB).…”

Section: Methodsmentioning

confidence: 91%

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants

et al. 2022

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Base editing (BE) can be applied to characterize single nucleotide variants (SNVs) of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular BE-activity ‘sensors’ that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor–sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated SNVs in multiple model systems. We demonstrate that sensor-validated tools streamline production of in vivo cancer models, and that integrating sensor modules in pooled sgRNA libraries can aid interpretation of high-throughput BE screens. Using this approach, we identify several previously uncharacterized mutant TP53 alleles as drivers of cancer cell proliferation and in vivo tumor development. We anticipate that the framework described here will facilitate the functional interrogation of cancer variants in cell and animal models.

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“…sgRNAs library cloning and screen deconvolution were performed as previously described 89,90 . Briefly, sgRNAs targeting the entire coding sequence of SS18 and SSX1 were designed using http://crispr.mit.edu/ and Benchling (https://benchling.com) and cloned into pLKO-U6-sgRNA-improved-EF1s-GFP-P2A (gifted by Darjus F Tschaharganeh).…”

Section: Methodsmentioning

confidence: 99%

An autoregulatory feedback loop converging on H2A ubiquitination drives synovial sarcoma

Benabdallah

Dalal

Sotiriou

et al. 2022

Preprint

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The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of mSWI/SNF complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the SSX C-terminus, via its SSXRD domain, directs SS18-SSX chromatin binding independently of SS18. SSXRD specific targeting is mediated by interaction with mono ubiquitinated H2A (H2AK119ub1) and histone MacroH2A with which the fusion overlaps genome wide. Variant Polycomb Repressive Complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C-terminus not only depends on H2AK119ub1 for localization but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results reveal an SSX/PRC1 autoregulatory feedback loop that reinforces fusion chromatin binding and therefore its oncogenic activity, and could play a role in a wider range of cancers and physiological settings where SSX proteins are overexpressed.

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A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition

Cited by 4 publications

References 133 publications

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants

An autoregulatory feedback loop converging on H2A ubiquitination drives synovial sarcoma

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