Similar to other fields, recent advances in the study of Sin3 have answered a few very important questions and generated additional thoughts, which, if addressed, will further fill the gap in the existing knowledge. Within the scope of this review, we identify some future directions for research. For instance, both, defined biochemical and biophysical studies are needed to better understand the mechanisms and circumstances in which Sin3 functions as a scaffold. Surprisingly, for instance, a better mapping of the interaction of Sin3 and HDAC is needed. Similarly, how the interactions between these molecules are affected by signaling and how these proteins join Sin3a to perform its function represent an interesting niche for research. Furthermore, how many Sin3 complexes exist and in which context they work remain to be extensively addressed. For instance, we currently know that some proteins, which are part of the basic transcriptional machine, form complexes that are tissue-specific (tissue-specific TATA binding proteins). We predict that this Sin3-mediated cell-specific mechanism exists, though final proof of this phenomenon and as to what extent it works remains to be determined. Lastly, a plethora of structural studies are still needed to define, at the molecular level, how different proteins interact with each other within the complex to perform defined functions. Therefore, just studying the biochemistry and biophysics of the Sin3 molecules are very promising areas of future investigation.
Another important conceptual framework that is lacking in the field is whether Sin3 repression is independent, or it initiates a gene silencing process that is completed by other silencing machines. In fact, Sin3a has been unexpectedly linked with both short- and long-term repression, therefore, the mechanism underlying this phenomenon warrants these investigations.
Noteworthy, a significant area of cell biological interest is whether the three different Sin3 isoforms have redundant and/or different functions. For instance, the short Sin3B isoform could potentially work as a dominant negative since it contains the PAH1 and 2 domains but lacks the HDAC-recruiting module. On the other hand, however, it is possible that this isoform still represses by recruiting HDACs via other signaling complexes. In addition, carefully analysis of Sin3a and Sin3b isoforms predict a similar biochemical function as scaffolds, but they show different sites for posttranslational modifications which lead us to predict that signaling-induced regulation may differentially influence the function of these proteins. Although some of these studies are already underway, we are far from clarifying this area of knowledge and therefore, significant efforts must be devoted to better understand why higher eukaryotes have evolved to have three different isoforms of Sin3.
Furthermore, studies on Sin3 targets are currently underdeveloped, and in particular, those examining how either the sequence-specific transcription factors or the Sin3 complexes are modulated by distinct membrane-to-nucleus signaling to achieve their biological role. The results of these studies are important to build meaningful pathways for predicting potential novel functions of Sin3, which will advance our understanding of the cell biological function of this transcriptional scaffold.
Studies on Sin3 association with other histone deacetylase complexes also warrant further attention. During the last two decades, it has been clearly demonstrated that other silencing molecules interact with members of the Sin3 complex. However, the specific molecular details of these interactions and their cell biological consequences remain poorly understood. Therefore, addressing these questions will illuminate how these interactions exert a synergistic or antagonistic effect on gene expression, physiology and/or pathobiology of human diseases.
HDAC inhibitors have gained a significant interest due to their role as potential therapeutic tools to fight neoplastic diseases. However, we currently know that some of the HDAC-associated complexes function as tumor suppressors, while others as oncogenes. These concepts support the idea that current HDAC inhibitors, which rely on inhibiting the enzymatic activities of these enzymes, may bring about significant side-effects and give rise to drugs with poor therapeutic index. Thus, the discovery of a new generation of more specific HDAC inhibitors is needed and theoretically feasible if more specific knowledge is generated as to how HDAC, Sin3, and other associated signaling molecules form complexes. The major concept would be to target specific HDAC interactions, with other silencing machines that use them as their mechanism of action, to derive new drugs. For instance, one can envision that the interaction between HDAC and Sin3a can specifically be disrupted without interfering with the N-CoR-HDAC interaction, thus avoiding undesirable effects. Therefore, we predict that we are at the beginning of an explosion of knowledge in this important area of research with significant medical relevance.
In summary, we here mention few, but extremely important new directions. We are excited with the possibilities that addressing these questions may bring as new knowledge. More importantly, these areas need to be explored to gain a better understanding of the cell and pathobiological contributions of Sin3, as well as the mechanisms underlying these functions. The discovery of Sin3 and its subsequent biochemical and mechanistic elucidation have already constituted a major advance in the field of transcriptional repression. The functional repertoire of Sin3 continues to expand at a rapid rate. The incredible flexibility afforded by the modular nature of the Sin3/HDAC complex provides Sin3 with unparalleled control in regulating gene transcription.