Spi-1/PU.1 activates transcription through clustered DNA occupancy in erythroleukemia.
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.
Institut Curie, Paris, F-75248, France.
Maya
M
Ridinger-Saison
Valentina
V
Boeva
Pauline
P
Rimmelé
Ivan
I
Kulakovskiy
Isabelle
I
Gallais
Benjamin
B
Levavasseur
Caroline
C
Paccard
Patricia
P
Legoix-Né
François
F
Morlé
Alain
A
Nicolas
Philippe
P
Hupé
Emmanuel
E
Barillot
Françoise
F
Moreau-Gachelin
Christel
C
Guillouf
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D059372:Nucleotide Motifs; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000378:metabolism*; D024363:Transcription Initiation Site; D015533:Transcriptional Activation; D000099232:Proto-Oncogene Protein Spi-1
D004247:DNA; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1