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The functional annotation and exploration the SOX11 enhanceosome

(2020)
Author
Organization
Abstract
Background/Introduction Neuroblastoma (NB) is the most common extra cranial solid tumor during early childhood, arising from progenitors of the sympathetic nervous system. We identified the adrenergic specific transcription factor SOX11 as a lineage dependency factor and a putative master regulator of epigenetic plasticity in NB. The expression of lineage identity genes is typically regulated by cell type specific enhancers thereby acting as putative cell-specific vulnerabilities that may be targeted while minimizing harm to the normal development of tissues. Aims We aimed to gain insight into the long-range control of SOX11 expression in NB cells as a first step towards cell type specific therapeutic targeting of SOX11-driven neuroblastoma. Methods/Materials We analyzed H3K27ac data to map noncoding regulatory enhancer regions in the vicinity of the SOX11 locus. Chromatin conformation analysis (4C-seq) additionally shows evidence for looping contacts between the SOX11 promotor region and the SILC1 locus, a lncRNA downstream of SOX11. For further exploration of the function of SILC1, chromatin isolation by RNA purification (ChIRP) is performed to identify lncRNA bound DNA sequences. Functional inhibition of the SILC1 locus is explored using dCas9-KRAB silencing in NB cells. Results We identified a super-enhancer in a large gene poor region, 1.1 Mb distal to the SOX11 locus. This region coincides with the previously annotated lncRNA coined SILC1 which was shown to be implicated in neurite outgrowth and neuron regeneration. SILC1 was found to be strongly expressed in adrenergic NB cells while absent in mesenchymal NB cells and highly correlated to SOX11 expression levels in both NB cell lines and tumors. Also, in the normal developing sympathetic lineage, SILC1 expression pattern closely resembled that of SOX11. Using 4C-seq, we observed looping in this highly active region between the SOX11 and SILC1 promoter in adrenergic NB cells while absent in the mesenchymal NB cell line SH-EP. We are currently unraveling the role of SILC1 using ChIRP sequencing and a dCas9-KRAB silencing system. Summary/conclusion In conclusion, our data suggests that SILC1 plays a crucial role in assisting the function of the transcription factor SOX11 thus offering an entry point for targeted therapy for SOX11-driven neuroblastoma.

Citation

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MLA
Louwagie, Amber, et al. The Functional Annotation and Exploration the SOX11 Enhanceosome. 2020.
APA
Louwagie, A., Decaesteker, B., Delhaye, L., D’haene, E., de Bony de Lavergne, E., Olexiouk, V., … Speleman, F. (2020). The functional annotation and exploration the SOX11 enhanceosome. Presented at the Advances in Neuroblastoma Research (ANR) 2020, Beurs van Berlage, Amsterdam.
Chicago author-date
Louwagie, Amber, Bieke Decaesteker, Louis Delhaye, Eva D’haene, Eric de Bony de Lavergne, Volodimir Olexiouk, Sarah Vergult, et al. 2020. “The Functional Annotation and Exploration the SOX11 Enhanceosome.” In .
Chicago author-date (all authors)
Louwagie, Amber, Bieke Decaesteker, Louis Delhaye, Eva D’haene, Eric de Bony de Lavergne, Volodimir Olexiouk, Sarah Vergult, Rogier Versteeg, Jan Koster, Johan van Nes, Sara Ek, Stephen Roberts, Sven Eyckerman, Pieter Mestdagh, Katleen De Preter, and Franki Speleman. 2020. “The Functional Annotation and Exploration the SOX11 Enhanceosome.” In .
Vancouver
1.
Louwagie A, Decaesteker B, Delhaye L, D’haene E, de Bony de Lavergne E, Olexiouk V, et al. The functional annotation and exploration the SOX11 enhanceosome. In 2020.
IEEE
[1]
A. Louwagie et al., “The functional annotation and exploration the SOX11 enhanceosome,” presented at the Advances in Neuroblastoma Research (ANR) 2020, Beurs van Berlage, Amsterdam, 2020.
@inproceedings{8642346,
  abstract     = {Background/Introduction
Neuroblastoma (NB) is the most common extra cranial solid tumor during early childhood, arising from progenitors of the sympathetic nervous system. We identified the adrenergic specific transcription factor SOX11 as a lineage dependency factor and a putative master regulator of epigenetic plasticity in NB. The expression of lineage identity genes is typically regulated by cell type specific enhancers thereby acting as putative cell-specific vulnerabilities that may be targeted while minimizing harm to the normal development of tissues.  
Aims
We aimed to gain insight into the long-range control of SOX11 expression in NB cells as a first step towards cell type specific therapeutic targeting of SOX11-driven neuroblastoma.
Methods/Materials
We analyzed H3K27ac data to map noncoding regulatory enhancer regions in the vicinity of the SOX11 locus. Chromatin conformation analysis (4C-seq) additionally shows evidence for looping contacts between the SOX11 promotor region and the SILC1 locus, a lncRNA downstream of SOX11. For further exploration of the function of SILC1, chromatin isolation by RNA purification (ChIRP) is performed to identify lncRNA bound DNA sequences. Functional inhibition of the SILC1 locus is explored using dCas9-KRAB silencing in NB cells.
Results
We identified a super-enhancer in a large gene poor region, 1.1 Mb distal to the SOX11 locus. This region coincides with the previously annotated lncRNA coined SILC1 which was shown to be implicated in neurite outgrowth and neuron regeneration. SILC1 was found to be strongly expressed in adrenergic NB cells while absent in mesenchymal NB cells and highly correlated to SOX11 expression levels in both NB cell lines and tumors. Also, in the normal developing sympathetic lineage, SILC1 expression pattern closely resembled that of SOX11. Using 4C-seq, we observed looping in this highly active region between the SOX11 and SILC1 promoter in adrenergic NB cells while absent in the mesenchymal NB cell line SH-EP. We are currently unraveling the role of SILC1 using ChIRP sequencing and a dCas9-KRAB silencing system.
Summary/conclusion
In conclusion, our data suggests that SILC1 plays a crucial role in assisting the function of the transcription factor SOX11 thus offering an entry point for targeted therapy for SOX11-driven neuroblastoma. 
},
  author       = {Louwagie, Amber and Decaesteker, Bieke and Delhaye, Louis and D'haene, Eva and de Bony de Lavergne, Eric and Olexiouk, Volodimir and Vergult, Sarah and Versteeg, Rogier and Koster, Jan and van Nes, Johan and Ek, Sara and Roberts, Stephen and Eyckerman, Sven and Mestdagh, Pieter and De Preter, Katleen and Speleman, Franki},
  location     = { Beurs van Berlage, Amsterdam},
  title        = {The functional annotation and exploration the SOX11 enhanceosome},
  year         = {2020},
}