Genome-wide chromatin profiles of PBRM1 [ChIP-Seq]. Genome-wide chromatin profiles of PBRM1 [ChIP-Seq]

PBRM1 encodes an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been well examined. Here we show that in VHL-deficient renal tumors, PBRM1 deficiency results in aberrant PBAF complexes that localize to de novo genomic loci and activate the pro-tumorigenic NF-?B pathway. PBRM1-deficient PBAF complexes, despite retaining the association between SMARCA4 and ARID2, have loosely tethered BRD7 and redistribute from promoter proximal regions to distal enhancers containing NF-?B motifs. Subsequently, PBRM1-deficient cells display heightened NF-?B activity in multiple models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib reverses NF-?B activation by reducing RELA occupancy and delays growth of PBRM1-deficient tumors. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-?B target genes by residual PBRM1-deficient PBAF complexes. Overall design: Comparison of chromatin changes with and without PBRM1

PBRM1编码SWI/SNF染色质重塑复合物PBAF亚类的辅助亚基，而PBRM1功能失活是肾癌中第二常见的突变事件。然而，PBRM1缺失对染色质重塑的影响，尤其是与肾癌肿瘤发生相关的机制，尚未得到充分研究。本研究发现，在VHL缺陷型肾肿瘤中，PBRM1缺失会导致异常PBAF复合物形成，该复合物会定位至新生基因组位点并激活促肿瘤发生的NF-κB通路。尽管保留了与SMARCA4和ARID2的相互作用，PBRM1缺陷型PBAF复合物的BRD7结合却变得松散，并从启动子近端区域重新分布至含有NF-κB基序的远端增强子区域。随后，在多种模型及临床样本中，PBRM1缺陷细胞均表现出NF-κB活性升高。SMARCA4的ATP酶功能可维持PBRM1缺失特异性产生的预存在及新获得的RELA的染色质占位，并激活下游靶基因的表达。蛋白酶体抑制剂硼替佐米（bortezomib）可通过降低RELA的染色质占位逆转NF-κB激活，并延缓PBRM1缺陷型肿瘤的生长。综上，PBRM1通过抑制残余的PBRM1缺陷型PBAF复合物异常释放促肿瘤发生的NF-κB靶基因，从而守护染色质稳态。实验整体设计：对比存在PBRM1与缺失PBRM1时的染色质变化。