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A SUMO-regulated activation function controls synergy of c-Myb through a repressor-activator switch leading to differential p300 recruitment.

Molvaersmyr AK, Saether T, Gilfillan S, Lorenzo PI, Kvaløy H, Matre V, Gabrielsen OS - Nucleic Acids Res. (2010)

Bottom Line: Focusing on the haematopoietic transcription factor c-Myb, we found evidence for a strong SC linked to SUMO-conjugation in its negative regulatory domain (NRD), while AMV v-Myb has escaped this control.When NRD is sumoylated, the activity of c-Myb is reduced.We therefore propose a general model for SUMO-mediated SC, where SUMO controls synergy by determining the number and strength of AFs associated with a promoter leading to differential chromatin signatures.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences, University of Oslo, Oslo, Norway.

ABSTRACT
Synergy between transcription factors operating together on complex promoters is a key aspect of gene activation. The ability of specific factors to synergize is restricted by sumoylation (synergy control, SC). Focusing on the haematopoietic transcription factor c-Myb, we found evidence for a strong SC linked to SUMO-conjugation in its negative regulatory domain (NRD), while AMV v-Myb has escaped this control. Mechanistic studies revealed a SUMO-dependent switch in the function of NRD. When NRD is sumoylated, the activity of c-Myb is reduced. When sumoylation is abolished, NRD switches into being activating, providing the factor with a second activation function (AF). Thus, c-Myb harbours two AFs, one that is constitutively active and one in the NRD being SUMO-regulated (SRAF). This double AF augments c-Myb synergy at compound natural promoters. A similar SUMO-dependent switch was observed in the regulatory domains of Sp3 and p53. We show that the change in synergy behaviour correlates with a SUMO-dependent differential recruitment of p300 and a corresponding local change in histone H3 and H4 acetylation. We therefore propose a general model for SUMO-mediated SC, where SUMO controls synergy by determining the number and strength of AFs associated with a promoter leading to differential chromatin signatures.

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A model for SRAF and SC. (A) A model for the repressed state, where SUMO-conjugation disrupts the interaction with the co-activator. (B) A model for the repressed state where multiple SUMO-conjugated factors recruit a multivalent co-repressor; SCF, synergy control factor (9). (C) Traditional concept of synergy mediated by joint recruitment of a multivalent co-activator. (D) Current model for the activated state where multiple AFs (depicted as stars) per transcription factor lead to more efficient recruitment of a multivalent co-activator. (E) A variant of the model above (D) where different AFs may interact with different co-activators.
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Figure 10: A model for SRAF and SC. (A) A model for the repressed state, where SUMO-conjugation disrupts the interaction with the co-activator. (B) A model for the repressed state where multiple SUMO-conjugated factors recruit a multivalent co-repressor; SCF, synergy control factor (9). (C) Traditional concept of synergy mediated by joint recruitment of a multivalent co-activator. (D) Current model for the activated state where multiple AFs (depicted as stars) per transcription factor lead to more efficient recruitment of a multivalent co-activator. (E) A variant of the model above (D) where different AFs may interact with different co-activators.

Mentions: Figure 10 illustrates some key elements in a model of transcriptional synergy. In the sumoylated state, synergy is restricted either because of a SUMO-induced blocking of productive interactions with co-activators (Figure 10A) or a SUMO-induced generation of repressive interactions (Figure 10B). A combination of both is also quite likely. The recruitment of repressors to chromatin fits very well with the model of SUMO-mediated heterochromatin formation (33), as well as with other repressor studies (50). Although not emphasized in the model, the work on SUMO-governed hetrochromatic formation (33) was performed with the same integrated, multimerized Gal4-responsive reporter gene as in this study. Thus, we would not be surprised if some of the co-repressors reported in Suske’s study turn out to have a preference for arrays of SUMO-conjugated factors. The active synergistic state would require removal of SUMO, which may be either a stochastic process caused by the unstable sumoylated state or a more directed process through signal-induced recruitment of SUMO-proteases.Figure 10.


A SUMO-regulated activation function controls synergy of c-Myb through a repressor-activator switch leading to differential p300 recruitment.

Molvaersmyr AK, Saether T, Gilfillan S, Lorenzo PI, Kvaløy H, Matre V, Gabrielsen OS - Nucleic Acids Res. (2010)

A model for SRAF and SC. (A) A model for the repressed state, where SUMO-conjugation disrupts the interaction with the co-activator. (B) A model for the repressed state where multiple SUMO-conjugated factors recruit a multivalent co-repressor; SCF, synergy control factor (9). (C) Traditional concept of synergy mediated by joint recruitment of a multivalent co-activator. (D) Current model for the activated state where multiple AFs (depicted as stars) per transcription factor lead to more efficient recruitment of a multivalent co-activator. (E) A variant of the model above (D) where different AFs may interact with different co-activators.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2926607&req=5

Figure 10: A model for SRAF and SC. (A) A model for the repressed state, where SUMO-conjugation disrupts the interaction with the co-activator. (B) A model for the repressed state where multiple SUMO-conjugated factors recruit a multivalent co-repressor; SCF, synergy control factor (9). (C) Traditional concept of synergy mediated by joint recruitment of a multivalent co-activator. (D) Current model for the activated state where multiple AFs (depicted as stars) per transcription factor lead to more efficient recruitment of a multivalent co-activator. (E) A variant of the model above (D) where different AFs may interact with different co-activators.
Mentions: Figure 10 illustrates some key elements in a model of transcriptional synergy. In the sumoylated state, synergy is restricted either because of a SUMO-induced blocking of productive interactions with co-activators (Figure 10A) or a SUMO-induced generation of repressive interactions (Figure 10B). A combination of both is also quite likely. The recruitment of repressors to chromatin fits very well with the model of SUMO-mediated heterochromatin formation (33), as well as with other repressor studies (50). Although not emphasized in the model, the work on SUMO-governed hetrochromatic formation (33) was performed with the same integrated, multimerized Gal4-responsive reporter gene as in this study. Thus, we would not be surprised if some of the co-repressors reported in Suske’s study turn out to have a preference for arrays of SUMO-conjugated factors. The active synergistic state would require removal of SUMO, which may be either a stochastic process caused by the unstable sumoylated state or a more directed process through signal-induced recruitment of SUMO-proteases.Figure 10.

Bottom Line: Focusing on the haematopoietic transcription factor c-Myb, we found evidence for a strong SC linked to SUMO-conjugation in its negative regulatory domain (NRD), while AMV v-Myb has escaped this control.When NRD is sumoylated, the activity of c-Myb is reduced.We therefore propose a general model for SUMO-mediated SC, where SUMO controls synergy by determining the number and strength of AFs associated with a promoter leading to differential chromatin signatures.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences, University of Oslo, Oslo, Norway.

ABSTRACT
Synergy between transcription factors operating together on complex promoters is a key aspect of gene activation. The ability of specific factors to synergize is restricted by sumoylation (synergy control, SC). Focusing on the haematopoietic transcription factor c-Myb, we found evidence for a strong SC linked to SUMO-conjugation in its negative regulatory domain (NRD), while AMV v-Myb has escaped this control. Mechanistic studies revealed a SUMO-dependent switch in the function of NRD. When NRD is sumoylated, the activity of c-Myb is reduced. When sumoylation is abolished, NRD switches into being activating, providing the factor with a second activation function (AF). Thus, c-Myb harbours two AFs, one that is constitutively active and one in the NRD being SUMO-regulated (SRAF). This double AF augments c-Myb synergy at compound natural promoters. A similar SUMO-dependent switch was observed in the regulatory domains of Sp3 and p53. We show that the change in synergy behaviour correlates with a SUMO-dependent differential recruitment of p300 and a corresponding local change in histone H3 and H4 acetylation. We therefore propose a general model for SUMO-mediated SC, where SUMO controls synergy by determining the number and strength of AFs associated with a promoter leading to differential chromatin signatures.

Show MeSH