Network-based, cross-cohort discovery of transcriptional mechanisms presiding over maintenance of high-risk neuroblastoma subtype state

Network-based analysis of neuroblastoma samples from two large cohorts identified master regulator proteins controlling the transcriptional state of three high-risk molecular subtypes. In particular, a TEAD4-MYCN positive feedback loop emerged as the core regulatory motif of a small protein module presiding over implementation and stability of the subtype associated with MYCN amplification. Specifically, MYCN transcriptionally activates TEAD4, which in turn activates MYCN both transcriptionally and post-translationally. The resulting MYCN-TEAD4 positive feedback loop plays a critical role in maintaining aberrant activity of a 10-protein regulatory module that causally regulates the transcriptional state of this subtype. Consistently, loss of TEAD4 activity induces core module activity collapse and abrogates neuroblastoma cell viability in vitro and in vivo, thus suggesting novel therapeutic strategies for this important childhood cancer. Overall design: Study of the transcriptional control by TEAD4 and MYCN positive feedback loop using RNA-seq profiles of TEAD4, WWTR1 and MYCN shRNA knockdowns in neuroblastoma BE2 cells. ChIP-Seq analysis using TEAD4 antibody in BE2 cells.

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Rajbhandari P, Lopez G, Capdevila C, Salvatori B, Yu J, Rodriguez-Barrueco R, Martinez D, Yarmarkovich M, Weichert-Leahey N, Abraham BJ, Alvarez MJ, Iyer A, Harenza JL, Oldridge D, De Preter K, Koster J, Asgharzadeh S, Seeger RC, Wei JS, Khan J, Vandesompele J, Mestdagh P, Versteeg R, Look AT, Young RA, Iavarone A, Lasorella A, Silva JM, Maris JM, Califano A