Si Yang, Bon Corentin, Barbachowska Magdalena, Cadet-Daniel Veronique, Jallet Corinne, Soresinetti Laura, Boullé Mikaël, Duchateau Magalie, Matondo Mariette, Agou Fabrice, Halby Ludovic, Arimondo Paola B
Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR3523 CNRS 75015 Paris France
Ecole Doctorale MTCI, Université de Paris, Sorbonne Paris Cité Paris France.
RSC Chem Biol. 2022 Feb 22;3(4):456-467. doi: 10.1039/d1cb00095k. eCollection 2022 Apr 6.
Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in human diseases such as cancer, thus the enzymes that establish epigenetic marks, such as histone methyltransferases (HMTs), are potentially therapeutic targets. Noteworthily, HMTs form multiprotein complexes that in concert regulate gene expression. To probe epigenetic protein complexes regulation in cells, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries simultaneously on multiple histone marks inside cells. By this approach, we identified that compound 4, a published CARM1 inhibitor, inhibits both histone mark H3R2me2a, regulated also by CARM1, and H3K79me2, regulated only by DOT1L, pointing out a crosstalk between CARM1 and DOT1L. Based on this interaction, we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger inhibition of cell proliferation and increase in apoptosis, indicating that our approach identifies possible effective synergistic drug combinations.
表观遗传调控是一个控制基因表达的动态且可逆的过程。其功能异常会导致诸如癌症等人类疾病，因此，诸如组蛋白甲基转移酶（HMTs）等建立表观遗传标记的酶有可能成为治疗靶点。值得注意的是，HMTs形成多蛋白复合物，协同调节基因表达。为了探究细胞内表观遗传蛋白复合物的调控机制，我们开发了一种可靠的化学生物学高内涵成像策略，用于在细胞内同时针对多种组蛋白标记筛选化合物库。通过这种方法，我们发现已报道的CARM1抑制剂化合物4，既能抑制同样受CARM1调控的组蛋白标记H3R2me2a，也能抑制仅受DOT1L调控的H3K79me2，这表明CARM1和DOT1L之间存在相互作用。基于这种相互作用，我们将化合物4与DOT1L抑制剂EPZ - 5676联合使用，结果对细胞增殖产生了更强的抑制作用，并增加了细胞凋亡，这表明我们的方法能够识别出可能有效的协同药物组合。
