Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity.

Autor: Dreijerink KMA; Department of Endocrinology, Amsterdam UMC, Amsterdam, The Netherlands., Ozyerli-Goknar E; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany., Koidl S; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany., van der Lelij EJ; Department of Endocrinology, Amsterdam UMC, Amsterdam, The Netherlands., van den Heuvel P; School of Life Sciences, and Research Group of Technologies of Analyses in Life Sciences (ATLS), Avans University of Applied Sciences, Breda, The Netherlands., Kooijman JJ; School of Life Sciences, and Research Group of Technologies of Analyses in Life Sciences (ATLS), Avans University of Applied Sciences, Breda, The Netherlands.; Oncolines B.V., Oss, The Netherlands., Biniossek ML; Institute for Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany., Rodenburg KW; School of Life Sciences, and Research Group of Technologies of Analyses in Life Sciences (ATLS), Avans University of Applied Sciences, Breda, The Netherlands., Nizamuddin S; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany., Timmers HTM; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.timmers@dkfz-heidelberg.de.; Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany. m.timmers@dkfz-heidelberg.de.
Jazyk: angličtina
Zdroj: Epigenetics & chromatin [Epigenetics Chromatin] 2022 Aug 09; Vol. 15 (1), pp. 29. Date of Electronic Publication: 2022 Aug 09.
DOI: 10.1186/s13072-022-00461-8
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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