PXD013353

PXD013353 is an original dataset announced via ProteomeXchange.

Title	Probing the Tumour Suppressor Function of BAP1 in CRISPR-engineered Human Liver Organoids
Description	The deubiquitinating enzyme BAP1 is a tumour suppressor, amongst others involved in cholangiocarcinoma. BAP1 has many proposed molecular targets, while its Drosophila homolog is known to deubiquitinate Histone H2AK119. Here, we mutate BAP1 by CRISPR/Cas9 in normal human liver organoids. We find that BAP1 controls the expression of junctional/cytoskeleton components by regulating chromatin accessibility. Consequently, we observe loss of multiple epithelial characteristics, while motility increases. Importantly, restoring the catalytic activity of BAP1 in the nucleus rescues these cellular and molecular changes. We engineer human liver organoids to combine four common cholangiocarcinoma mutations (TP53, PTEN, SMAD4, NF1). In this genetic background, BAP1 loss results in acquisition of malignant features upon xenotransplantation. Thus, control of epithelial identity through the regulation of chromatin accessibility appears a key aspect of BAP1’s tumour suppressor function. Organoid technology combined with CRISPR/Cas9 provides an experimental platform for mechanistic studies of cancer gene function in a human context.
HostingRepository	PRIDE
AnnounceDate	2019-05-22
AnnouncementXML	Submission_2019-08-29_06:38:28.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rik Lindeboom
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; N-acylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-03 03:45:56	ID requested
1	2019-05-22 09:25:10	announced
⏵ 2	2019-08-29 06:38:29	announced	Updated publication reference for PubMed record(s): 31130514.

Artegiani B, van Voorthuijsen L, Lindeboom RGH, Seinstra D, Heo I, Tapia P, L, ó, pez-Iglesias C, Postrach D, Dayton T, Oka R, Hu H, van Boxtel R, van Es JH, Offerhaus J, Peters PJ, van Rheenen J, Vermeulen M, Clevers H, Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids. Cell Stem Cell, 24(6):927-943.e6(2019) [pubmed]

submitter keyword: human liver organoids, CRISPR-Cas9, Human Cholangiocarcinoma, BAP1, multiomics, human tumor modelling

Hans Clevers
contact affiliation	Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, The Netherlands
contact email	h.clevers@hubrecht.eu
lab head
Rik Lindeboom
contact affiliation	Radboud Institute for Molecular Life Sciences
contact email	r.lindeboom@science.ru.nl
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/2019/05/PXD013353

PRIDE project URI

• PRIDE
  1. PXD013353
     1. Label: PRIDE project
     2. Name: Probing the Tumour Suppressor Function of BAP1 in CRISPR-engineered Human Liver Organoids