The Chromatin Remodeling Factor Mi-2α Acts as a Novel Co-activator for Human c-Myb

Abstract

The c-Myb protein belongs to a group of early hematopoietic transcription factors that are important for progenitor generation and proliferation. These factors have been hypothesized to participate in establishing chromatin patterns specific for hematopoietic genes. In a two-hybrid screening we identified the chromatin remodeling factor Mi-2␣ as an interaction partner for human c-Myb. The main interacting domains were mapped to the N-terminal region of Mi-2␣ and the DNA-binding domain of c-Myb. Surprisingly, functional analysis revealed that Mi-2␣, previously studied as a subunit in the NuRD corepressor complex, enhanced c-Myb-dependent reporter activation. Consistently, knock-down of endogenous Mi-2␣ in c-Myb-expressing K562 cells, led to down-regulation of the c-Myb target genes NMU and ADA. When wild-type and helicase-dead Mi-2␣ were compared, the Myb-Mi-2␣ co-activation appeared to be independent of the ATPase/DNA helicase activity of Mi-2␣. The rationale for the unexpected co-activator function seems to lie in a dual function of Mi-2␣, by which this factor is able to repress transcription in a helicase-dependent and activate in a helicase-independent fashion, as revealed by Gal4-tethering experiments. Interestingly, desumoylation of c-Myb potentiated the Myb-Mi-2␣ transactivational co-operation, as did co-transfection with p300.

AML with translocation t(8;16)(p11;p13) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features

“…53 Recently, in a two-hybrid screening CHD3 was identified as an interaction partner for human c-Myb and gain of the MYB locus was found as recurrent abnormality in AML with t(8;16) cases using array comparative genome hybridization technology. 54 Thus, one can speculate that aberrant expression of CHD3 would perturb the MYB pathway and therefore may contribute to a maturation block in monocyte-macrophage differentiation as reported previously. 55 Using a classification analysis we were able to demonstrate that AML with t(8;16) harbors underlying gene expression signatures that are robust enough to also serve as a potential classifier to predict new cases of AML with t(8;16).…”

The Histone Acetyltransferase TIP60 Interacts with c-Myb and Inactivates Its Transcriptional Activity in Human Leukemia

“…Notably, c-Myb-associated p300/CBP, MLL, and Mi-2 chromatin-modifying proteins are required for the activation of c-Myb target genes (21,27,28). Meanwhile, corepressors TIF1, mSin3A, c-Ski, and N-CoR bind to c-Myb and block the trans-activating activity of c-Myb, suppressing the potential oncogenic properties of c-Myb (29).…”

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

“…Moreover, the transcriptional regulatory activity of Myb is crucial for its transforming ability (Gonda et al, 1989;Lane et al, 1990;Hu et al, 1991). Multiple co-factors like p300/CBP, Mi-2a, FLASH and menin/MLL engage in the regulation of the transactivational activity of c-Myb (Dai et al, 1996;Oelgeschlager et al, 1996;Kasper et al, 2002;Saether et al, 2007;Alm-Kristiansen et al, 2008;Jin et al, 2010). Recently, the importance of coactivation by p300 in myeloid transformation was highlighted using a novel murine hematopoietic cell line transformation assay (Pattabiraman et al, 2009).…”