Myc oncogene is a transcription factor that contributes to the genesis of a wide variety of tumors by regulating proliferation, differentiation and apoptosis. Despite being one of the first isolated oncogene, the biochemical mechanisms of Myc mediated transcriptional regulation remain unclear. Myc has been found to govern different aspects of gene expression, from chromatin remodeling to basal transcription and processive RNAPII elongation. Myc binding to targets genes depends on the presence of the E-box binding motif and the presence of histone H3K4me3 lysine.

We provide recent findings regarding the function of Myc in orchestrating different steps in transcription, and we propose a model that links histone H3 methylation code to Myc target genes. Myc upon binding to the E box trigger a series of events that assembles the transcription initiation complex, recruits the demethylating enzyme, LSD1, induces DNA oxidation and chromating looping. Once started RNAPII still needs Myc assistance during transcription elongation.

Myc seems to modulate at least two crucial steps in transcription. i.e. chromatin modifications for initiation and RNAPII pause release for productive elongation. P-TEFb-Myc interaction (see below).

Myc regulates  also RNAPII post-initiation regulatory events. We found Myc associated to the cyclin T component of the transcription elongation complex P-TEFb, composed by the heterodimer CDK9/cyclinT1 and demonstrated that release of RNA Polymerase II pausing and transcriptional elongation entered is one of the molecular mechanisms for Myc mediated activated transcription

MYCN and LSD1 in  Neuroblastoma

The chromatin-modifying enzyme lysine-specific demethylase 1, KDM1A/LSD1 is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells and its overexpression correlated with aggressive disease, poor differentiation and infaust outcome. Here, we show that LSD1 physically binds MYCN both in vitro and in vivo and that such an interaction requires the MYCN BoxIII. We found that LSD1 co-localizes with MYCN on promoter regions of CDKN1A/p21 and Clusterin (CLU) suppressor genes and cooperates with MYCN to repress the expression of these genes. KDM1A needs to engage with MYCN in order to associate with the CDKN1A and CLU promoters. The expression of CLU and CDKN1A can be restored in MYCN-amplified cells by pharmacological inhibition of LSD1 activity or knockdown of its expression. Combined pharmacological inhibition of MYCN and LSD1 through the use of small molecule inhibitors synergistically reduces MYCN-amplified Neuroblastoma cell viability in vitro. These findings demonstrate that LSD1 is a critical co-factor of the MYCN repressive function, and suggest that combination of LSD1 and MYCN inhibitors may have strong therapeutic relevance to counteract MYCN-driven oncogenesis