PXD023548

PXD023548 is an original dataset announced via ProteomeXchange.

Title	A phase separation mechanism underlies development of cancer and aberrant organization of three-dimensional chromatin structure
Description	Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin’s IDR, tandemly dispersed phenylalanine-andglycine (FG) repeats1-3. However, it remains largely elusive how unstructured IDRs contribute to oncogenesis. We here show that IDR or FG repeats harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in acute leukemia patients1,4,5, is essential for establishing nuclear liquid-liquid phase separation (LLPS) puncta and for inducing leukemic transformation of primary hematopoietic cells in vitro and in vivo. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TF oncoproteins but is also required for formation of a broad, ‘super-enhancer’-like binding pattern, typically seen at a battery of leukemia-related loci exemplified by HOX, MEIS and PBX genes, potentiating their transcriptional activation. An artificial HOX chimera, created by replacing NUP98’s FG repeats with an unrelated LLPSforming IDR of FUS6,7, had similar enhancement effects on chimera’s chromatin binding and target gene activation. Via Hi-C mapping, we further demonstrated that the phase-separated NUP98-HOXA9 protein assembly is able to induce formation of CTCF-independent chromatin looping enriched at leukemic oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish condensates of oncogenic TFs via a phase separation mechanism, which simultaneously enhances their chromatin targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As a range of LLPS-competent molecules are implicated in various human cancers, this mechanism can potentially be generalized to many malignant and diseased settings.
HostingRepository	PRIDE
AnnounceDate	2021-04-22
AnnouncementXML	Submission_2021-07-26_09:30:07.042.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD023548
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Stephanie Byrum
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-12 06:25:07	ID requested
1	2021-04-22 05:53:23	announced
⏵ 2	2021-07-26 09:30:08	announced	2021-07-26: Updated publication reference for PubMed record(s): 34163069.

Ahn JH, Davis ES, Daugird TA, Zhao S, Quiroga IY, Uryu H, Li J, Storey AJ, Tsai YH, Keeley DP, Mackintosh SG, Edmondson RD, Byrum SD, Cai L, Tackett AJ, Zheng D, Legant WR, Phanstiel DH, Wang GG, Phase separation drives aberrant chromatin looping and cancer development. Nature, 595(7868):591-595(2021) [pubmed]

submitter keyword: intrinsically disordered regions (IDRs), BioID, oncogenesis, homeodomain-containing transcription factor

Gang Greg Wang
contact affiliation	1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. 2Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. 3Biological and Biomedical Sciences Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
contact email	greg_wang@med.unc.edu
lab head
Stephanie Byrum
contact affiliation	UAMS
contact email	sbyrum@uams.edu
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/2021/04/PXD023548

PRIDE project URI

• PRIDE
  1. PXD023548
     1. Label: PRIDE project
     2. Name: A phase separation mechanism underlies development of cancer and aberrant organization of three-dimensional chromatin structure