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Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as
Koen M A Dreijerink1, Ezgi Ozyerli-Goknar2,3, Stefanie Koidl2,3
1Department of Endocrinology, Amsterdam UMC, Amsterdam, The Netherlands.
Background:
Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors.
Results:
Here, we applied and in silico screening approach for 253 disease-related MEN1 missense mutations in order to select a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/MLL2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the MLL1 and MLL2 interactions when compared with JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites.
Conclusions:
Our results underline the effects of MEN1 gene mutations in both familial and sporadic tumors of endocrine origin on the interactions of menin with the MLL1 and MLL2 histone H3K4 methyltransferase complexes and with JunD-containing transcription factors. Menin binding pocket mutants R52G, E255K and E359K have differential effects on MLL1/MLL2 and JunD interactions, which translate into differential genomic binding patterns. Our findings encourage future studies addressing the pathophysiological relevance of the separate MLL1/MLL2- and JunD-dependent functions of menin mutants in MEN1 disease model systems.
Insights
Multiple endocrine neoplasia type 1 (MEN1) gene mutations disrupt menin protein interactions with MLL1/MLL2 and JunD. Specific MEN1 mutants differentially affect these interactions, impacting genomic binding and potentially contributing to MEN1 tumor syndrome.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Loss-of-function mutations in the multiple endocrine neoplasia type 1 (MEN1) gene cause MEN1 tumor syndrome and are implicated in sporadic neuroendocrine tumors and other cancers.
- The MEN1 gene product, menin, is crucial for transcriptional and chromatin regulation, functioning within COMPASS-like complexes (MLL1/MLL2) and interacting with transcription factors like JunD.
- Menin's dual role in regulating gene expression through distinct protein complexes is central to its function and dysfunction in disease.
Purpose of the Study:
- To investigate the impact of MEN1 missense mutations on menin's interactions with MLL1/MLL2 and JunD.
- To identify specific mutations that differentially affect menin's binding to these key protein partners.
- To understand how these altered interactions may contribute to the pathogenesis of MEN1-related tumors.
Main Methods:
- In silico screening of 253 disease-related MEN1 missense mutations to identify surface-exposed residues.
- Quantitative mass spectrometry to assess the protein interactomes of nine selected menin mutants.
- Analysis of mutant protein binding to specific genomic sites associated with MLL1 and JunD.
Main Results:
- Seven out of nine tested menin mutants disrupted interactions with both MLL1/MLL2 and JunD complexes.
- Three specific mutations (R52G, E255K, E359K) predominantly weakened interactions with MLL1/MLL2 compared to JunD.
- These three mutants showed reduced binding at MLL1 genomic sites with less impact on JunD binding sites.
Conclusions:
- MEN1 gene mutations significantly affect menin's interactions with MLL1/MLL2 and JunD, relevant to both familial and sporadic endocrine tumors.
- Menin binding pocket mutants (R52G, E255K, E359K) exhibit differential effects on MLL1/MLL2 and JunD interactions, leading to distinct genomic binding patterns.
- Further research into the pathophysiological significance of these separate MLL1/MLL2- and JunD-dependent functions of menin mutants is warranted for MEN1 disease models.
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