Ikaros interacts with P-TEFb and cooperates with GATA-1 to enhance transcription elongation.
Ikaros is associated with both gene transcriptional activation and repression in lymphocytes. Ikaros acts also as repressor of human γ-globin (huγ-) gene transcription in fetal and adult erythroid cells. Whether and eventually, how Ikaros can function as a transcriptional activator in erythroid cells remains poorly understood. Results presented herein demonstrate that Ikaros is a developmental-specific activator of huγ-gene expression in yolk sac erythroid cells. Molecular analysis in primary cells revealed that Ikaros interacts with Gata-1 and favors Brg1 recruitment to the human β-globin Locus Control Region and the huγ-promoters, supporting long-range chromatin interactions between these regions. Additionally, we demonstrate that Ikaros contributes to transcription initiation and elongation of the huγ-genes, since it is not only required for TBP and RNA Polymerase II (Pol II) assembly at the huγ-promoters but also for conversion of Pol II into the elongation-competent phosphorylated form. In agreement with the latter, we show that Ikaros interacts with Cyclin-dependent kinase 9 (Cdk9), which contributes to efficient transcription elongation by phosphorylating the C-terminal domain of the large subunit of Pol II on Serine 2, and favours Cdk9 recruitment to huγ-promoters. Our results show that Ikaros exerts dual functionality during gene activation, by promoting efficient transcription initiation and elongation.
Maisonneuve-Rosemont Hospital Research Center, Maisonneuve-Rosemont Hospital and Faculty of Medicine, University of Montreal, 5415 boulevard l'Assomption, Montreal, Quebec, Canada H1T 2M4.
Stefania
S
Bottardi
Farah A
FA
Zmiri
Vincent
V
Bourgoin
Julie
J
Ross
Lionel
L
Mavoungou
Eric
E
Milot
D000818:Animals; D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D019901:Locus Control Region; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015017:Yolk Sac / Q000033:anatomy & histology / Q000254:growth & development; D005719:gamma-Globulins / Q000235:genetics / Q000378:metabolism
D050982:GATA1 Transcription Factor; D009687:Nuclear Proteins; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D005719:gamma-Globulins; D051740:Ikaros Transcription Factor; D042925:Positive Transcriptional Elongation Factor B; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
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