Proteomics

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PBRM1-deficient PBAF complexes target de novo genomic loci to activate pro-survival genes in clear cell renal cell carcinoma (PBRM1 dataset)

ABSTRACT: PBRM1 is lost in 40% of clear cell renal cell carcinomas (ccRCC) and the combined loss of VHL and PBRM1 drives ccRCC tumorigenesis. PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and despite its well-established role as a tumor suppressor, we have limited understanding of how PBRM1 regulates the chromatin. Now we report that PBRM1 binds to promoter-proxy regions with footprints at +1 to + 3 nucleosomes. PBRM1-deficient PBAF complexes lose BRD7 but retain ARID2, while tethered to SMARCA4. The lack of PBRM1-BRD7 module compromises the targeting specificity of the PBAF complexes, causes their genomic redistribution and impairs the repressive ability of PBAF complexes. Subsequently, PBRM1-deficient PBAF complexes prime the chromatin at de novo sites for transcriptional activation of pro-survival genes involved in hypoxia and cholesterol synthesis. Therefore, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-survival genes by residual PBRM1-deficient SWI/SNF complexes.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Xiaosai Yao 

PROVIDER: PXD020554 | JPOST Repository | Sat Jul 24 00:00:00 BST 2021

REPOSITORIES: jPOST

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Publications

PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma.

Yao Xiaosai X   Hong Jing Han JH   Nargund Amrita M AM   Ng Michelle Shu Wen MSW   Heng Hong Lee HL   Li Zhimei Z   Guan Peiyong P   Sugiura Masahiro M   Chu Pek Lim PL   Wang Loo Chien LC   Ye Xiaofen X   Qu James J   Kwek Xiu Yi XY   Lim Jeffrey Chun Tatt JCT   Ooi Wen Fong WF   Koh Joanna J   Wang Zhenxun Z   Pan You-Fu YF   Ong Yan Shan YS   Tan Kiat-Yi KY   Goh Jian Yuan JY   Ng Sheng Rong SR   Pignata Luca L   Huang Dachuan D   Lezhava Alexander A   Tay Su Ting ST   Lee Minghui M   Yeo Xun Hui XH   Tam Wai Leong WL   Rha Sun Young SY   Li Shang S   Guccione Ernesto E   Futreal Andrew A   Tan Jing J   Yeong Joe Poh Sheng JPS   Hong Wanjin W   Yauch Robert R   Chang Kenneth Tou-En KT   Sobota Radoslaw M RM   Tan Patrick P   Teh Bin Tean BT  

Nature cell biology 20230424 5

PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway. PBRM1-deficient PBAF complexes retain the association between SMARCA4 and ARID2, but h  ...[more]

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