Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation.
The transcription factor GATA-1 participates in programming the differentiation of multiple hematopoietic lineages. In megakaryopoiesis, loss of GATA-1 function produces complex developmental abnormalities and underlies the pathogenesis of megakaryocytic leukemia in Down syndrome. Its distinct functions in megakaryocyte and erythroid maturation remain incompletely understood. In this study, we identified functional and physical interaction of GATA-1 with components of the positive transcriptional elongation factor P-TEFb, a complex containing cyclin T1 and the cyclin-dependent kinase 9 (Cdk9). Megakaryocytic induction was associated with dynamic changes in endogenous P-TEFb composition, including recruitment of GATA-1 and dissociation of HEXIM1, a Cdk9 inhibitor. shRNA knockdowns and pharmacologic inhibition both confirmed contribution of Cdk9 activity to megakaryocytic differentiation. In mice with megakaryocytic GATA-1 deficiency, Cdk9 inhibition produced a fulminant but reversible megakaryoblastic disorder reminiscent of the transient myeloproliferative disorder of Down syndrome. P-TEFb has previously been implicated in promoting elongation of paused RNA polymerase II and in programming hypertrophic differentiation of cardiomyocytes. Our results offer evidence for P-TEFb cross-talk with GATA-1 in megakaryocytic differentiation, a program with parallels to cardiomyocyte hypertrophy.
Elagib
Kamaleldin E
KE
Department of Pathology, University of Virginia School of Medicine, Charlottesville, USA.
Mihaylov
Ivailo S
IS
Delehanty
Lorrie L
LL
Bullock
Grant C
GC
Ouma
Kevin D
KD
Caronia
Jill F
JF
Gonias
Sara L
SL
Goldfarb
Adam N
AN
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000502:physiology*; D004314:Down Syndrome; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D020239:Receptor Cross-Talk
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D042925:Positive Transcriptional Elongation Factor B; D042863:Cyclin-Dependent Kinase 9
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