000 | 02729 am a22004333u 4500 | ||
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042 | _adc | ||
100 | 1 | 0 |
_aSparbier, Christina E. _eauthor _93068 |
700 | 1 | 0 |
_aGillespie, Andrea _eauthor _93069 |
700 | 1 | 0 |
_aGomez, Juliana _eauthor _93070 |
700 | 1 | 0 |
_aKumari, Nishi _eauthor _93071 |
700 | 1 | 0 |
_aMotazedian, Ali _eauthor _93072 |
700 | 1 | 0 |
_aChan, Kah Lok _eauthor _93073 |
700 | 1 | 0 |
_aBell, Charles C. _eauthor _93074 |
700 | 1 | 0 |
_aGilan, Omer _eauthor _93075 |
700 | 1 | 0 |
_aChan, Yih-Chih _eauthor _93076 |
700 | 1 | 0 |
_aPopp, Sarah _eauthor _93077 |
700 | 1 | 0 |
_aGough, Daniel J. _eauthor _93078 |
700 | 1 | 0 |
_aEckersley-Maslin, Melanie A. _eauthor _93079 |
700 | 1 | 0 |
_aDawson, Sarah-Jane _eauthor _93080 |
700 | 1 | 0 |
_aLehner, Paul J. _eauthor _93081 |
700 | 1 | 0 |
_aSutherland, Kate D. _eauthor _93082 |
700 | 1 | 0 |
_aErnst, Patricia _eauthor _93083 |
700 | 1 | 0 |
_aMcGeehan, Gerard M. _eauthor _93084 |
700 | 1 | 0 |
_aLam, Enid Y. N. _eauthor _93085 |
700 | 1 | 0 |
_aBurr, Marian L. _eauthor _93086 |
700 | 1 | 0 |
_aDawson, Mark A. _eauthor _93087 |
245 | 0 | 0 | _aTargeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes |
260 | _c2023-02. | ||
500 | _a/pmc/articles/PMC7614190/ | ||
500 | _a/pubmed/36635503 | ||
520 | _aPrecise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and is frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole genome CRISPR/Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin-KMT2A/B complexes in maintaining bivalency. Unexpectedly, genetic loss or pharmacological inhibition of Menin phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. Whilst Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals therapeutic opportunities that can be leveraged through inhibition of Menin. | ||
540 | _a | ||
540 | _ahttps://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license. | ||
546 | _aen | ||
690 | _aArticle | ||
655 | 7 |
_aText _2local |
|
786 | 0 | _nNat Cell Biol | |
856 | 4 | 1 |
_uhttp://dx.doi.org/10.1038/s41556-022-01056-x _zConnect to this object online. |
999 |
_c999 _d999 |