CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Nat Genet. 2021 Mar;53(3):269-278. doi: 10.1038/s41588-021-00777-3. Epub 2021 Feb 8.
Cancer-associated, loss-of-function mutations in genes encoding subunits of the BRG1/BRM-associated factor (BAF) chromatin-remodeling complexes often cause drastic chromatin accessibility changes, especially in important regulatory regions. However, it remains unknown how these changes are established over time (for example, immediate consequences or long-term adaptations), and whether they are causative for intracomplex synthetic lethalities, abrogating the formation or activity of BAF complexes. In the present study, we use the dTAG system to induce acute degradation of BAF subunits and show that chromatin alterations are established faster than the duration of one cell cycle. Using a pharmacological inhibitor and a chemical degrader of the BAF complex ATPase subunits, we show that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in an almost complete loss of chromatin accessibility at BAF-controlled sites, especially also at superenhancers, providing a mechanism for intracomplex synthetic lethalities.
癌症相关的、BRG1/BRM 相关因子（BAF）染色质重塑复合物亚基编码基因的失活功能突变常常导致剧烈的染色质可及性变化，特别是在重要的调控区域。然而，这些变化是如何随着时间的推移建立的（例如，即时后果或长期适应），以及它们是否是导致复合物内合成致死的原因，从而破坏 BAF 复合物的形成或活性，目前仍不清楚。在本研究中，我们使用 dTAG 系统诱导 BAF 亚基的急性降解，并表明染色质改变的建立速度快于一个细胞周期的持续时间。使用药理学抑制剂和 BAF 复合物 ATP 酶亚基的化学降解剂，我们表明维持基因组可及性需要不断的 ATP 依赖性重塑。在缺乏同源物的背景下，通过急性降解一个合成致死亚基完全消除 BAF 复合物的功能，导致 BAF 控制的位点，尤其是超级增强子，染色质可及性几乎完全丧失，为复合物内合成致死提供了一种机制。
