The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma

Banito, Ana; Li, Xiang; Laporte, Aimée N.; Roe, Jae Seok; Sanchez‐Vega, Francisco; Huang, Chen‐Hung; Dancsok, Amanda R.; Hatzi, Katerina; Chen, Chi Chao; Tschaharganeh, Darjus F.; Chandwani, Rohit; Tasdemir, Nilgun; Jones, Kevin B.; Capecchi, Mario R.; Vakoc, Christopher R.; Schultz, Nikolaus; Ladanyi, Marc; Nielsen, Torsten O.; Lowe, Scott W.

doi:10.1016/j.ccell.2018.07.006

Cited by 56 publications

(93 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This co-occurrence can persist, even in species where PRDM9 is not believed to position DSBs, suggesting the co-operation between these proteins does not completely depend on this aspect of PRDM9's function. Interestingly, such a SET domain of PRDM9 mainly occurs when PRDM9 possesses a SSXRD domain, which in other proteins (Banito et al, 2018) recruits CXXC2 which binds to CpG islands -whether this connects to our observation of a potential CpGbinding domain in ZCWPW1, and CpG-binding behaviour ex-vivo, remains to be explored.…”

Section: Discussionmentioning

confidence: 93%

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

View full text Add to dashboard Cite

During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified.We identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons.Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility. Graphical Abstract LegendIn humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

show abstract

Section: Discussionmentioning

confidence: 93%

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…SSX genes are a family of CTAs involved in transcriptional repression (14)(15)(16)(17). The resulting SS18-SSX oncoprotein leads to massive dysregulation of the chromatin architecture and transcriptional regulation (11,(18)(19)(20), generating a spectrum of malignant cellular morphologies (4), including counterparts (immune and stroma) grouped primarily by cell type (Fig. 1B,C), as we have observed in other tumor types (28)(29)(30).…”

Section: Introductionmentioning

confidence: 86%

“…Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies. epithelial-like malignant cells (in biphasic tumors), suggestive of pluripotential differentiation or mesenchymal to epithelial transitions.Studies of human SyS to date have either relied on bulk tissue (21,22) or on established cellular models (11,18,19), masking important aspects of the tumor ecosystem. Moreover, given this cancer's rarity, even concerted efforts, such as TCGA, profiled only limited numbers of tumors (21-23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma

Jerby‐Arnon

Neftel

Shore

et al. 2019

Preprint

View full text Add to dashboard Cite

Synovial sarcoma is an aggressive mesenchymal neoplasm, driven by the SS18-SSX fusion, and characterized by immunogenic antigens expression and exceptionally low T cell infiltration levels.To study the cancer-immune interplay in this disease, we profiled 16,872 cells from 12 human synovial sarcoma tumors using single-cell RNA-sequencing (scRNA-Seq). Synovial sarcoma manifests antitumor immunity, high cellular plasticity and a core oncogenic program, which is predictive of low immune levels and poor clinical outcomes. Using genetic and pharmacological perturbations, we demonstrate that the program is controlled by the SS18-SSX driver and repressed by cytokines secreted by macrophages and T cells in the tumor microenvironment. Network modeling predicted that SS18-SSX promotes the program through HDAC1 and CDK6. Indeed, the combination of HDAC and CDK4/6 inhibitors represses the program, induces immunogenic cell states, and selectively targets synovial sarcoma cells. Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies. epithelial-like malignant cells (in biphasic tumors), suggestive of pluripotential differentiation or mesenchymal to epithelial transitions.Studies of human SyS to date have either relied on bulk tissue (21,22) or on established cellular models (11,18,19), masking important aspects of the tumor ecosystem. Moreover, given this cancer's rarity, even concerted efforts, such as TCGA, profiled only limited numbers of tumors (21-23). Here, we leveraged single-cell RNA-Seq (scRNA-Seq), imaging, functional perturbations, and computational modeling, to study the cancer-immune interplay in SyS. We profiled 16,872 cells from 12 human SyS tumors by scRNA-seq and demonstrate that SyS tumors invariably include a subpopulation of cells expressing a novel core oncogenic program, associated with T cell exclusion. The core oncogenic program is predictive of poor prognosis and is repressed by the genetic inhibition of the SS18-SSX fusion, and by cytokines expressed by T cells and macrophages in the tumor microenvironment. HDAC1 and CDK6 are a key regulator and target of this aggressive cell program, respectively, and their combined inhibition synergistically represses it in SyS cells, triggering antigen presentation and cell autonomous immune responses.Collectively, our findings demonstrate a strong connection between SyS development and immune evasion, and strengthen the notion that de-differentiation, immune evasion, and cell cycle are coregulated, such that cellular immunity can be targeted through modulation of cell cycle and epigenetic processes. RESULTS Cell type inference from expression and genetic features in scRNA-seq of SySTo comprehensively interrogate the SyS ecosystem, we used full-length (24) and droplet-based (25) scRNA-Seq to profile 16,872 high quality malignant, immune, and stromal cells from 12 human SyS tumors ( Fig. 1A,B, Supp. Fig. 1A,B, Supp. Table 1, Methods). We assigned...

show abstract

“…We found an enriched family of testis-specific proteins specifically expressed at this time characterized by the presence of both SSXRD and KRABrelated domains. The SSXRD domain has been studied in the context of synovial sarcomas where it was found to associate with the CpG binding protein CXXC2 (KDM2B) which is a component of a non-canonical polycomb complex 38 . Interestingly another non-canonical polycomb component Dcaf7 also has a high loading in component 20 39 .…”

Section: De Novo Inference Of Transcription Factor Binding Sitesmentioning

confidence: 99%

Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains

Jung¹,

Wells

Rusch³

et al. 2018

Preprint

View full text Add to dashboard Cite

By removing the confounding factor of cellular heterogeneity, single cell genomics can revolutionize the study of development and disease, but methods are needed to simplify comparison among individuals. To develop such a framework, we assayed the transcriptome in 62,600 single cells from the testes of wildtype mice, and mice with gonadal defects due to disruption of the genes Mlh3, Hormad1, Cul4a or Cnp. The resulting expression atlas of distinct cell clusters revealed novel markers and new insights into testis gene regulation. By jointly analysing mutant and wildtype cells using a model-based factor analysis method, SDA, we decomposed our data into 46 components that identify novel meiotic gene regulatory programmes, mutant-specific pathological processes, and technical effects. Moreover, we identify, de novo, DNA sequence motifs associated with each component, and show that SDA

show abstract

The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma

Cited by 56 publications

References 0 publications

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma

Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains

Contact Info

Product

Resources

About