Abstract
The transcription factor MYB is a master regulator in haematopoietic progenitor cells and a pioneer factor affecting differentiation and proliferation of these cells. Leukaemic transformation may be promoted by high MYB levels. Despite much accumulated molecular knowledge of MYB, we still lack a comprehensive understanding of its target genes and its chromatin action. In the present work, we performed a ChIP-seq analysis of MYB in K562 cells accompanied by detailed bioinformatics analyses. We found that MYB occupies both promoters and enhancers. Five clusters (C1–C5) were found when we classified MYB peaks according to epigenetic profiles. C1 was enriched for promoters and C2 dominated by enhancers. C2-linked genes were connected to hematopoietic specific functions and had GATA factor motifs as second in frequency. C1 had in addition to MYB-motifs a significant frequency of ETS-related motifs. Combining ChIP-seq data with RNA-seq data allowed us to identify direct MYB target genes. We also compared ChIP-seq data with digital genomic footprinting. MYB is occupying nearly a third of the super-enhancers in K562. Finally, we concluded that MYB cooperates with a subset of the other highly expressed TFs in this cell line, as expected for a master regulator.
Highlights
The transcription factor MYB is a master regulator in haematopoietic progenitor cells and a pioneer factor affecting differentiation and proliferation of these cells
Leukaemic transformation may be promoted in cases where high MYB levels are maintained[1,13], which is the case in many human lymphoid and myeloid acute leukaemias[14], where MYB may act as a critical mediator of oncogene addiction[15]
Through its transactivation domain (tAD), MYB interacts with the KIX-domain of the histone acetyl transferases p300 and CBP17–21, an interaction which is required for the induction of acute myeloid leukemia (AML) and appears to be a promising therapeutic target for AML treatment[22]
Summary
The transcription factor MYB is a master regulator in haematopoietic progenitor cells and a pioneer factor affecting differentiation and proliferation of these cells. Two studies have shown that the MYB DBD, in addition to binding to DNA, interacts with histone tails[26,27,28]. MYB occupies genomic loci of its target genes. In the model the N-terminal DNA binding domain (DBD), the central transactivation domain (tAD) and the C-terminal regulatory domain (CRD) of MYB are shown. Left panel shows a line plot showing the intensity of MYB ChIP-seq signals centred at the TSS of all genes. Myb ChIP-seq peaks show occupancy at BENC and PVT1 enhancer regions located downstream of the MYC gene. Visualization of the tracks were made using the UCSC genome b rowser[76] (https://genome.ucsc.edu/) by creating a UCSC session containing the K562 control and MYB ChIP-seq bigwig files from the current study
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