Spi-1/PU.1 activates transcription through clustered DNA occupancy in erythroleukemia

Nucleic Acids Res. 2012 Oct;40(18):8927-41. doi: 10.1093/nar/gks659. Epub 2012 Jul 11.


Acute leukemias are characterized by deregulation of transcriptional networks that control the lineage specificity of gene expression. The aberrant overexpression of the Spi-1/PU.1 transcription factor leads to erythroleukemia. To determine how Spi-1 mechanistically influences the transcriptional program, we combined a ChIP-seq analysis with transcriptional profiling in cells from an erythroleukemic mouse model. We show that Spi-1 displays a selective DNA-binding that does not often cause transcriptional modulation. We report that Spi-1 controls transcriptional activation and repression partially through distinct Spi-1 recruitment to chromatin. We revealed several parameters impacting on Spi-1-mediated transcriptional activation. Gene activation is facilitated by Spi-1 occupancy close to transcriptional starting site of genes devoid of CGIs. Moreover, in those regions Spi-1 acts by binding to multiple motifs tightly clustered and with similar orientation. Finally, in contrast to the myeloid and lymphoid B cells in which Spi-1 exerts a physiological activity, in the erythroleukemic cells, lineage-specific cooperating factors do not play a prevalent role in Spi-1-mediated transcriptional activation. Thus, our work describes a new mechanism of gene activation through clustered site occupancy of Spi-1 particularly relevant in regard to the strong expression of Spi-1 in the erythroleukemic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • CpG Islands
  • DNA / chemistry
  • DNA / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genome
  • Leukemia, Erythroblastic, Acute / genetics*
  • Leukemia, Erythroblastic, Acute / metabolism
  • Mice
  • Mice, Transgenic
  • Nucleotide Motifs
  • Proto-Oncogene Proteins / metabolism*
  • Regulatory Elements, Transcriptional*
  • Sequence Analysis, DNA
  • Trans-Activators / metabolism*
  • Transcription Initiation Site
  • Transcriptional Activation*


  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • DNA