TMPRSS2–ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer

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Abstract

Mathieu Lupien and colleagues analyze data from primary prostate tumors with and without TMPRSS2–ERG (T2E) rearrangements. They find that in T2E tumors, there is a distinct regulatory landscape resulting from the co-option of transcription factors by ERG which causes dependency on NOTCH signaling.

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Most cited references 42

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Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity.

Lingyun Song, Zhancheng Zhang, Linda L Grasfeder … (2011)

The human body contains thousands of unique cell types, each with specialized functions. Cell identity is governed in large part by gene transcription programs, which are determined by regulatory elements encoded in DNA. To identify regulatory elements active in seven cell lines representative of diverse human cell types, we used DNase-seq and FAIRE-seq (Formaldehyde Assisted Isolation of Regulatory Elements) to map "open chromatin." Over 870,000 DNaseI or FAIRE sites, which correspond tightly to nucleosome-depleted regions, were identified across the seven cell lines, covering nearly 9% of the genome. The combination of DNaseI and FAIRE is more effective than either assay alone in identifying likely regulatory elements, as judged by coincidence with transcription factor binding locations determined in the same cells. Open chromatin common to all seven cell types tended to be at or near transcription start sites and to be coincident with CTCF binding sites, while open chromatin sites found in only one cell type were typically located away from transcription start sites and contained DNA motifs recognized by regulators of cell-type identity. We show that open chromatin regions bound by CTCF are potent insulators. We identified clusters of open regulatory elements (COREs) that were physically near each other and whose appearance was coordinated among one or more cell types. Gene expression and RNA Pol II binding data support the hypothesis that COREs control gene activity required for the maintenance of cell-type identity. This publicly available atlas of regulatory elements may prove valuable in identifying noncoding DNA sequence variants that are causally linked to human disease.

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Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages.

E Scott, M Simon, J Anastasi … (1994)

The transcription factor PU.1 is a hematopoietic-specific member of the ets family. Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. Mutant embryos produced normal numbers of megakaryocytes and erythroid progenitors, but some showed an impairment of erythroblast maturation. An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor.

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A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth.

Qianben Wang, Wei Li, X Liu … (2007)

Androgen receptor (AR) is a ligand-dependent transcription factor that plays a key role in prostate cancer. Little is known about the nature of AR cis-regulatory sites in the human genome. We have mapped the AR binding regions on two chromosomes in human prostate cancer cells by combining chromatin immunoprecipitation (ChIP) with tiled oligonucleotide microarrays. We find that the majority of AR binding regions contain noncanonical AR-responsive elements (AREs). Importantly, we identify a noncanonical ARE as a cis-regulatory target of AR action in TMPRSS2, a gene fused to ETS transcription factors in the majority of prostate cancers. In addition, through the presence of enriched DNA-binding motifs, we find other transcription factors including GATA2 and Oct1 that cooperate in mediating the androgen response. These collaborating factors, together with AR, form a regulatory hierarchy that governs androgen-dependent gene expression and prostate cancer growth and offer potential new opportunities for therapeutic intervention.

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Author and article information

Journal

Title: Nature Genetics

Abbreviated Title: Nat Genet

Publisher: Springer Nature

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Created: August 7 2017

Publication date (Print): August 7 2017

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Article

DOI: 10.1038/ng.3930

PubMed ID: 28783165

SO-VID: 4ba40e23-7173-4862-9a3a-77047f0807b8

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TMPRSS2–ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer

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Neuronal Signaling

Most cited references 42

Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity.

Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages.

A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth.

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