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Gulf Coast Consortia

Speaker: Charles Lin
Assistant Professor, Department of Molecular and Human Genetics
Baylor College of Medicine

Keck Seminar, Charles Lin, Baylor College of Medicine

Friday, February 17, 2017
4:00 PM  to 12:00 PM

Auditorium  BioScience Research Collaborative
Rice University
6500 Main St
Houston, Texas, USA

Targeting MYCN Driven Transcription in Neuroblastoma In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates. It remains fundamentally unclear how elevated levels of MYCN occupy the genome and alter transcriptional programs in neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of direct MYCN perturbation in neuroblastoma. We find that at oncogenic levels, MYCN associates with E-box (CANNTG) binding motifs in an affinity dependent manner, binding to canonical (CACGTG) E-boxes at promoters and invading abundant weaker clustered E-box motifs at enhancers. MYCN shutdown globally reduces chromatin acetylation and transcription, consistent with prior descriptions of MYC proteins as non-linear amplifiers of gene expression. This non-linear response is shaped by MYCN enhancer invasion which occurs at the most highly occupied genes that are most sensitive to MYCN perturbation suggesting a key role for enhancers in predicating the often highly tumor specific “MYC target gene signatures”. At invaded enhancers, we identify the enhancer specifying bHLH TF TWIST1 as an oncogenic collaborator and dependency of MYCN in neuroblastoma suggesting targeting of the MYCN enhancer regulatory axis as a promising therapeutic strategy to counteract MYCN driven transcription.

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