Physical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxβ

Abstract

TFII-I family proteins are characterized structurally by the presence of multiple reiterated I-repeats, each containing a putative helix-loophelix domain. Functionally, they behave as multifunctional transcription factors that are activated by a variety of extracellular signals. In studying their subcellular localization, we noticed that these transcription factors frequently reside in subnuclear domains͞dots. Because nuclear dots are believed often to harbor components of histone deacetylase enzymes (HDACs), we investigated whether TFII-I family proteins colocalize and interact with HDACs. Here, we show that TFII-I and its related member hMusTRD1͞BEN physically and functionally interact with HDAC3. The TFII-I family proteins and HDAC3 also show nearly identical expression patterns in early mouse development. Consistent with our earlier observation that TFII-I family proteins also interact with PIASx␤, a member of the E3 ligase family involved in the small ubiquitin-like modifier (SUMO) pathway, we show further that PIASx␤ physically and functionally interacts with HDAC3 and relieves the transcriptional repression exerted by HDAC3 upon TFII-I-mediated gene activation. These results suggest a complex interplay between two posttranslational pathways-histone modification and SUMOylation-brokered in part by TFII-I family proteins. E xtracellular signals often are transduced to the nucleus to bring about either up-regulation or down-regulation of specific genes. However, because the nuclear DNA is packaged with histones in nucleosomal arrays, to initiate transcriptional activation of any given gene, the promoter DNA must be accessible by the gene-specific activators as well as the basal machinery. Conversely, an actively transcribing genetic locus or a specific gene can be '''switched off'' by rendering the DNA inaccessible. Hence, the regulation of gene expression may begin at the level of chromatin alteration by concerted actions of histonemodifying enzymes. A histone acetyl transferase (HAT) acts by acetylating the tails of histones, lowering their positive charge and decreasing its stability of interactions with the DNA, upon which DNA becomes accessible. A histone deacetylase (HDAC) can reverse such an effect by deacetylating the histones, preserving their basic nature and, thereby, impeding DNA accessibility (1-3). Several other histone-tail modifications also have been described, such as methylation, ubiquitination, and phosphorylation (2, 3). It has been proposed that certain combinations of these modifications in one or more tails act sequentially or concomitantly to form a ''histone code'' recognized by specific regulatory proteins that lead to downstream events (4). It is generally believed that these enzymes are brought to the vicinity of the DNA and targeted to specific promoter regions through interactions with transcription factors, which can exert their effect only when the DNA is accessible. Therefore, to better understand how these enzymes regulate gene expression, considerable efforts have been spe...

TFII-I: Connecting Mitogenic Signals to Cell Cycle Regulation

“…1). Because TFII-I is associated with chromatin modifying proteins, 50,51 it possibly mediates additional contacts for the recruitment of these proteins to DNA damage sites. If so, perhaps TFII-I links signal specificity to DNA repair.…”

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

“…These include nuclear hormone receptors, such as the androgen receptor (AR), p53, Smad4, Sp3, HMGI-C, Gfi-1, IRF-1, TFII-I and yeast septins (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). In mouse and man, four Pias genes (Pias1, Pias3, Piasx, and Piasy) have been identified, which encode proteins that share a similar domain structure but differ in their specificity of interaction with other proteins.…”

“…This observation could account for the repression of transcription factor activity without changes in DNA binding. In addition, PIASx␤ has been found to interact with histone deacetylase-3, which is involved in repression of TFII-I family proteins (25). The activation function of PIAS proteins could also be accounted for by the sumoylation-dependent augmentation of protein-protein interactions.…”

Signal-induced functions of the transcription factor TFII-I

“…However, the precise mechanism by which these dynamics are achieved upon mitogenic signaling remains unknown. The alteration in promoter occupancy by the two isoforms of TFII-I, together with their respective interactions with MAPK and HDACs (37)(38)(39)(40), perhaps provides a reasonable mechanism to explain the unusual dynamics of c-fos regulation. Moreover, TFII-I is also shown to be associated with histone demethylase co-repressor complex, LSD1/BHC110 (38).…”