PXD020544

PXD020544 is an original dataset announced via ProteomeXchange.

Title	PBRM1 loss in kidney cancer imbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation
Description	PBRM1 is the 2nd-most frequently inactivated gene in clear cell renal cell cancer (RCC) but the oncogenic mechanisms, and hence methods for correction, are unclear. PBRM1 is a subunit of the PBAF coactivator complex that transcription factors use to reposition nucleosomes (‘open chromatin’) for gene activation. We therefore looked for transcription factors that recruit endogenous PBRM1 in kidney lineage/RCC cells, as a waypoint to identifying pathways impacted by PBRM1 loss. Unbiased immunoprecipitation/mass-spectrometry analyses of the endogenous PBRM1 interactome in kidney lineage cells revealed PAX8, a master transcription factor essential for proximal tubule epithelial fates, as the major transcription factor recruiting PBRM1/PBAF. The reverse analyses of the PAX8 interactome confirmed recruitment specifically of PBRM1/PBAF, and not the functionally similar BAF coactivator complex. More conspicuous in the PAX8 hub in RCC cells, however, were several corepressors, e.g. DNMT1, which oppose coactivators to repress instead of activate genes. Accordingly, key PAX8 target genes, e.g., GATA3, LHX1, WT1, and ~1000 other downstream kidney epithelial genes, but not PAX8 or PAX2, demonstrated loss of the histone lysine 27 acetylation (H3K27ac) activation mark, increase in CpG methylation repression marks, and lower expression in RCC vs normal kidney cortex, with the greatest repression in cases with bi-allelic PBRM1 inactivation. PBRM1 re-introduction into RCC cells, or depletion of the corepressor DNMT1 using siRNA or a clinical drug decitabine, rebalanced composition and function of the PAX8 transcription factor hub to coactivators, to thereby activate terminal epithelial-fates in vitro and in vivo. In sum, PBRM1 loss in RCC cells skews coregulator composition of the PAX8 master transcription factor hub toward corepressors and repression instead of activation of the downstream terminal epithelial-program; this oncogenic action could be reversed by pharmacologic corepressor depletion/inhibition.
HostingRepository	PRIDE
AnnounceDate	2022-02-16
AnnouncementXML	Submission_2022-02-16_09:41:00.177.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaorong Gu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-23 17:47:23	ID requested
⏵ 1	2022-02-16 09:41:01	announced

Gu X, Enane F, Tohme R, Schuerger C, Radivoyevitch T, Parker Y, Zuberi E, Przychodzen B, Jha BK, Lindner D, Rini B, Saunthararajah Y, PBRM1 loss in kidney cancer unbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation. Cell Rep, 36(12):109747(2021) [pubmed]

submitter keyword: PBRM1 PAX8 Differentiation

Xiaorong Gu
contact affiliation	Cleveland Clinic
contact email	gux@ccf.org
lab head
Xiaorong Gu
contact affiliation	Cleveland Clinic
contact email	gux@ccf.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD020544

PRIDE project URI

• PRIDE
  1. PXD020544
     1. Label: PRIDE project
     2. Name: PBRM1 loss in kidney cancer imbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation