Research

We have found that components of the transcription apparatus regulate not only mRNA synthesis in the nucleus, but also mRNA translation and decay in the cytoplasm. Promoter elements (Bregman et al., 2011), “classical” transcription factors (e.g., Rap1) (Bregman et al., 2011) and even Pol II (Goler Baron et al., 2008) directly regulate mRNA degradation in the cytoplasm. Conversely, the  major decaysome, which degrades mRNAs in the cytoplasm, also fosters mRNA synthesis in the nucleus (Haimovich et al., 2013). Thus, we propose that mRNA synthesis and degradation processes are mediated by a single multifactorial mechanism, the synthegradosome, which shuttles between the chromatin and the cytoplasm (Haimovich et al., 2013). Even more unexpected was our finding that Pol II components regulate protein synthesis in the cytoplasm (Harel-sharvit et al., 2010). All the above discoveries defy the common wisdom by breaking the traditional long-established boundaries between the nuclear and the cytoplasmic processes. We began unravelling the mechanism underlying  this cross-talk, whereby components of the transcription apparatus bind to the mRNA co-transcriptionally (a phenomenon that they termed “mRNA imprinting”, see Choder 2011) and accompany the mRNA throughout its life, thereby regulating post-transcriptional stage(s) Goler Baron et al., 2008, Harel-sharvit et al., 2010Choder 2011).

Finally, we demonstrated that at least two factors, Rpb4 and Rpb7, originally identified as Pol II subunits, regulate ALL major stages of the mRNA lifecycle (reviewed in Choder, 2004, Choder, 2011 and Dahan & Choder, 2013), while shuttling between the nucleus and the cytoplasm (Selitrennik et al., 2007)). Importantly, mRNA imprinting by Rpb4 and Rpb7 can occur only in the context of Pol II. Hence, the capacity of these factors to function in post-transcriptional stages depends on their capacity to bind Pol II and to stimulate transcription (Goler Baron et al., 2008, Harel-Sharvit et al. 2010). This indicates that the major component of the transcription apparatus, Pol II, can regulate also mRNA translation and decay by recruiting these proteins. Interestingly, mRNA imprinting is a regulated process – responsive to the environment (Shalem et al., 2011). Taken together, these findings led us to propose that Rpb4 and Rpb7 function as “mRNA coordinators” that integrate all stages into a system. Rpb4 and Rpb7 are the first genuine mRNA coordinators, i.e., each of their post-transcriptional function is mechanistically coupled to their transcriptional one. Our yet unpublished work uncovered the existence of other mRNA coordinators that are specific to certain classes of mRNAs.

Another novel and unexpected discovery is that the proteins Rap1, Rpb4 and Rpb7 (and 2 additional unpublished factors) stimulate both the synthesis and the decay of mRNA transcripts. This let us to propose the concept of “synthegradases”.   We propose that such two-arm machineries represent a common theme in biology, not only in mRNA synthesis and decay.

In recent years, studies of single genes have evolved into analyses of network of genes to obtain a whole-genome view. We have initiated an analogous zooming out on molecular processes, thus shifting the field from studies of distinct processes (e.g., transcription, translation) to investigating how all these processes are interconnected and integrated in a manner that enables the cell to function as a system. Hence, our work has opened a new avenue in the field of gene expression, which we term “processomics”: focusing on the cross-talk between all distinct processes. The current processomics deals with the biochemistry of gene expression, but it has the potential to evolve into whole-cell and later whole-organism endeavor.