Signal transducer and activator of transcription STAT5 is recruited to c- Myc super-enhancer

Abstract

Background

c- Myc has been proposed as a putative target gene of signal transducer and activator of transcription 5 (STAT5). No functional STAT5 binding site has been identified so far within the c- Myc gene locus, therefore a direct transcriptional regulation by STAT5 remains uncertain. c- Myc super-enhancer, located 1.7 Mb downstream of the c- Myc gene locus, was recently reported as essential for the regulation of c- Myc gene expression by hematopoietic transcription factors and bromodomain and extra-terminal (BET) proteins and for leukemia maintenance. c- Myc super-enhancer is composed of five regulatory regions (E1–E5) which recruit transcription and chromatin-associated factors, mediating chromatin looping and interaction with the c- Myc promoter.

Results

We now show that STAT5 strongly binds to c- Myc super-enhancer regions E3 and E4, both in normal and transformed Ba/F3 cells. We also found that the BET protein bromodomain-containing protein 2 (BRD2), a co-factor of STAT5, co-localizes with STAT5 at E3/E4 in Ba/F3 cells transformed by the constitutively active STAT5-1*6 mutant, but not in non-transformed Ba/F3 cells. BRD2 binding at E3/E4 coincides with c- Myc transcriptional activation and is lost upon treatment with deacetylase and BET inhibitors, both of which inhibit STAT5 transcriptional activity and c- Myc gene expression.

Conclusions

Our data suggest that constitutive STAT5 binding to c- Myc super-enhancer might contribute to BRD2 maintenance and thus allow sustained expression of c- Myc in Ba/F3 cells transformed by STAT5-1*6.

Electronic supplementary material

The online version of this article (doi:10.1186/s12867-016-0063-y) contains supplementary material, which is available to authorized users.