TIF1alpha: a possible link between KRAB zinc finger proteins and nuclear receptors

Ligand-induced gene activation by nuclear receptors (NRs) is thought to be mediated by transcriptional intermediary factors (TIFs), that interact with their ligand-dependent AF-2 activating domain. Included in the group of the putative AF-2 TIFs identified so far is TIF1alpha, a member of a new family of proteins which contains an N-terminal RBCC (RING finger-B boxes-coiled coil) motif and a C-terminal bromodomain preceded by a PHD finger. In addition to these conserved domains present in a number of transcriptional regulatory proteins, TIF1alpha was found to contain several protein-protein interaction sites. Of these, one specifically interacts with NRs bound to their agonistic ligand and not with NR mutants that are defective in the AF-2 activity. Immediately adjacent to this 'NR box', TIF1alpha contains an interaction site for members of the chromatin organization modifier (chromo) family, HP1alpha and MOD1, which both are heterochromatinic proteins. Finally, TIF1alpha also has a binding site for KRAB silencing domains of C2H2 zinc finger proteins. TIF1beta, another member of the TIF1 gene family, has some interacting partners in common with TIF1alpha. TIF1beta can interact with HP1alpha, MOD1 and KRAB domains, but apparently not with NRs. Both TIF1alpha and TIF1beta repress transcription when fused to a DNA binding domain in transiently transfected mammalian cells. A model discussing the potential function(s) of TIF1s in the control of transcription at the level of the chromatin template will be presented.