PMID- 35941657 OWN - NLM STAT- MEDLINE DCOM- 20220810 LR - 20221101 IS - 1756-8935 (Electronic) IS - 1756-8935 (Linking) VI - 15 IP - 1 DP - 2022 Aug 9 TI - Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity. PG - 29 LID - 10.1186/s13072-022-00461-8 [doi] LID - 29 AB - 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. CI - (c) 2022. The Author(s). FAU - Dreijerink, Koen M A AU - Dreijerink KMA AD - Department of Endocrinology, Amsterdam UMC, Amsterdam, The Netherlands. FAU - Ozyerli-Goknar, Ezgi AU - Ozyerli-Goknar E AD - German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany. AD - Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany. FAU - Koidl, Stefanie AU - Koidl S AD - German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany. AD - Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany. FAU - van der Lelij, Ewoud J AU - van der Lelij EJ AD - Department of Endocrinology, Amsterdam UMC, Amsterdam, The Netherlands. FAU - van den Heuvel, Priscilla AU - van den Heuvel P AD - School of Life Sciences, and Research Group of Technologies of Analyses in Life Sciences (ATLS), Avans University of Applied Sciences, Breda, The Netherlands. FAU - Kooijman, Jeffrey J AU - Kooijman JJ AD - School of Life Sciences, and Research Group of Technologies of Analyses in Life Sciences (ATLS), Avans University of Applied Sciences, Breda, The Netherlands. AD - Oncolines B.V., Oss, The Netherlands. FAU - Biniossek, Martin L AU - Biniossek ML AD - Institute for Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany. FAU - Rodenburg, Kees W AU - Rodenburg KW AD - School of Life Sciences, and Research Group of Technologies of Analyses in Life Sciences (ATLS), Avans University of Applied Sciences, Breda, The Netherlands. FAU - Nizamuddin, Sheikh AU - Nizamuddin S AD - German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany. AD - Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany. FAU - Timmers, H T Marc AU - Timmers HTM AD - German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.timmers@dkfz-heidelberg.de. AD - Department of Urology, Medical Center -University of Freiburg, Freiburg, Germany. m.timmers@dkfz-heidelberg.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220809 PL - England TA - Epigenetics Chromatin JT - Epigenetics & chromatin JID - 101471619 RN - 0 (Histones) RN - 0 (JunD protein, human) RN - 0 (MEN1 protein, human) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Proto-Oncogene Proteins c-jun) RN - 0 (Transcription Factors) SB - IM MH - Histones/metabolism MH - Humans MH - *Multiple Endocrine Neoplasia Type 1/genetics/metabolism MH - Mutation, Missense MH - Proto-Oncogene Proteins/*genetics MH - Proto-Oncogene Proteins c-jun/genetics/metabolism MH - Transcription Factors/metabolism MH - Virulence PMC - PMC9361535 OTO - NOTNLM OT - AP-1 transcription factors OT - ATF transcription factors OT - CUT&RUN genome profiling OT - Histone H3K4 methylation OT - MEN1 syndrome OT - Quantitative mass spectrometry OT - Tumor suppressor COIS- The authors declare that they have no competing interest. EDAT- 2022/08/09 06:00 MHDA- 2022/08/11 06:00 PMCR- 2022/08/09 CRDT- 2022/08/08 23:51 PHST- 2022/06/27 00:00 [received] PHST- 2022/07/01 00:00 [accepted] PHST- 2022/08/08 23:51 [entrez] PHST- 2022/08/09 06:00 [pubmed] PHST- 2022/08/11 06:00 [medline] PHST- 2022/08/09 00:00 [pmc-release] AID - 10.1186/s13072-022-00461-8 [pii] AID - 461 [pii] AID - 10.1186/s13072-022-00461-8 [doi] PST - epublish SO - Epigenetics Chromatin. 2022 Aug 9;15(1):29. doi: 10.1186/s13072-022-00461-8.