Ikaros SUMOylation: Switching Out of Repression

Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 05/2005; 25(7):2688-97. DOI: 10.1128/MCB.25.7.2688-2697.2005
Source: PubMed


Ikaros plays a key role in lymphocyte development and homeostasis by both potentiating and repressing gene expression. Here we show that Ikaros interacts with components of the SUMO pathway and is SUMOylated in vivo. Two SUMOylation sites are identified on Ikaros whose simultaneous modification results in a loss of Ikaros' repression function. Ikaros SUMOylation disrupts its participation in both histone deacetylase (HDAC)-dependent and HDAC-independent repression but does not influence its nuclear localization into pericentromeric heterochromatin. These studies reveal a new dynamic way by which Ikaros-mediated gene repression is controlled by SUMOylation.

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Available from: Katia Georgopoulos, Aug 06, 2014
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    • "AF10 has also been shown to interact with FLRG and Ikaros, both of which have been implicated in hematopoiesis [24], [25], [26]. FLRG participates in erythrocytic commitment, whereas Ikaros interacts with chromatin remodeling factors and plays a role in transcriptional regulation and cell cycle control during lymphocyte differentiation [27], [28], [29], [30]. AF10 was recently shown to be present in a complex also containing Tcf4/β-catenin and Dot1L in mouse small intestinal crypts, zebrafish, and Drosophila, where it participates in the maintenance of intestinal cell homeostasis [31], [32]. "
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    ABSTRACT: Hematopoiesis is a complex process regulated by both cell intrinsic and cell extrinsic factors. Alterations in the expression of critical genes during hematopoiesis can modify the balance between stem cell differentiation and proliferation, and may ultimately give rise to leukemia and other diseases. AF10 is a transcription factor that has been implicated in the development of leukemia following chromosomal rearrangements between the AF10 gene and one of at least two other genes, MLL and CALM. The link between AF10 and leukemia, together with the known interactions between AF10 and hematopoietic regulators, suggests that AF10 may be important in hematopoiesis and in leukemic transformation. Here we show that AF10 is important for proper hematopoietic differentiation. The induction of hematopoietic differentiation in both human hematopoietic cell lines and murine total bone marrow cells triggers a decrease of AF10 mRNA and protein levels, particularly in stem cells and multipotent progenitors. Gain- and loss-of-function studies demonstrate that over- or under-expression of AF10 leads to apoptotic cell death in stem cells and multipotent progenitors. We conclude that AF10 plays a key role in the maintenance of multipotent hematopoietic cells.
    PLoS ONE 12/2012; 7(12):e51626. DOI:10.1371/journal.pone.0051626 · 3.23 Impact Factor
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    • "Mutations that abolished SUMOylation, or de-SUMOylation by SUMO peptidases strengthened the capacity of FOG-2 to repress the GATA-4-activated BNP promoter. Lack of SUMOylation leading to increased repression activity was previously observed in the erythroid transcription factor Ikaros [23]. Conversely, additional FOG-2 SUMOylation or expression of a SUMO-1-FOG2-4KR chimeric protein abrogated the repressive function of FOG-2 and FOG-2-4KR, respectively, linking SUMO to the modulation of FOG-2-mediated transcription. "
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    ABSTRACT: Friend of GATA 2 (FOG-2), a co-factor of several GATA transcription factors (GATA-4, -5 and 6), is a critical regulator of coronary vessel formation and heart morphogenesis. Here we demonstrate that FOG-2 is SUMOylated and that this modification modulates its transcriptional activity. FOG-2 SUMOylation occurs at four lysine residues (K312, 471, 915, 955). Three of these residues are part of the characteristic SUMO consensus site (ψKXE), while K955 is found in the less frequent TKXE motif. Absence of SUMOylation did not affect FOG-2's nuclear localization. However, mutation of the FOG-2 SUMOylation sites, or de-SUMOylation, with SENP-1 or SENP-8 resulted in stronger transcriptional repression activity in both heterologous cells and cardiomyocytes. Conversely, increased FOG-2 SUMOylation by overexpression of SUMO-1 or expression of a SUMO-1-FOG-2 fusion protein rendered FOG-2 incapable of repressing GATA-4-mediated activation of the B-type natriuretic peptide (BNP) promoter. Moreover, we demonstrate both increased interaction between a FOG-2 SUMO mutant and GATA-4 and enhanced SUMOylation of wild-type FOG-2 by co-expression of GATA-4. These data suggest a new dynamics in which GATA-4 may alter the activity of FOG-2 by influencing its SUMOylation status.
    PLoS ONE 11/2012; 7(11):e50637. DOI:10.1371/journal.pone.0050637 · 3.23 Impact Factor
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    • "Nevertheless, a significant fraction of Ikaros is associated with a Brg1-based SWI/SNF-like complex (10). The relevance of the latter interaction has been indicated by several observations: (i) Ikaros has been associated with gene activation mediated by SWI/SNF-like complexes in T cells (3); (ii) Ikaros co-fractionates and co-immunoprecipitates with Brg1 (10,13); and (iii) Ikaros and Brg1 are also components of a SWI/SNF-like complex in mouse erythroleukemia (MEL) cells (14). "
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    ABSTRACT: 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.
    Nucleic Acids Research 05/2011; 39(9):3505-19. DOI:10.1093/nar/gkq1271 · 9.11 Impact Factor
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