Cell Mol Life Sci
September 1, 2013;
Transcriptional regulation and nuclear reprogramming: roles of nuclear actin and actin-binding proteins.
Proper regulation of transcription is essential for cells to acquire and maintain cell identity. Transcriptional activation plays a central role in gene regulation and can be modulated by introducing transcriptional activators such as transcription factors. Activators act on their specific target genes to induce transcription. Reprogramming experiments have revealed that as cells become differentiated, some genes are highly silenced and even introduction of activators that target these silenced genes does not induce transcription. This can be explained by chromatin-based repression that restricts access of transcriptional activators to silenced genes. Transcriptional activation from these genes can be accomplished by opening chromatin, in addition to providing activators. Once a de novo transcription network is established, cells are differentiated or reprogrammed to a new cell type. Emerging evidence suggests that actin in the nucleus
(nuclear actin) and nuclear actin-binding proteins are implicated in these transcriptional regulatory processes. This review summarizes roles of nuclear actin and actin-binding proteins in transcriptional regulation. We also discuss possible functions of nuclear actin during reprogramming in the context of transcription and chromatin remodeling.
Cell Mol Life Sci
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Fig. 1. Silenced genes can be classified into two categories (activatable and occluded genes) depending on the resistance to transcriptional activation. After the addition of transcriptional activators, some of the previously silenced genes can start transcription (activatable genes). Silencing of such genes is likely due to the absence of activators and/or the presence of repressors and hence addition of activators allows transcriptional activation from those genes. In other words, activators have access to those genes to induce gene activation. In contrast, some genes are not activated even if known activators of these genes are present (occluded genes). This is probably because occluded genes are silenced by chromatin-based mechanisms that preclude access of activators to target genes. It seems to take a longer time for activators to finally gain access to such genes. This classification of genes in response to transcriptional activators has been proposed by Lahn and colleagues [26, 27]. Activation from occluded genes can be enhanced by adding chromatin remodeling factors and chromatin modifiers that can relieve these chromatin-based repression mechanisms
Fig. 2. RNA polymerase II transcription is regulated by nuclear actin and actin-binding proteins. A model of nuclear actin- and actin-binding protein-mediated transcription by RNA polymerase II. Nuclear actin has been shown to interact with many proteins that play crucial roles in Pol II-mediated transcription. Actin directly interacts with Pol II and is required for the pre-initiation complex formation. PSF forms a complex with NonO and N-WASP and this complex can bind to the Pol II C-terminal repeat domain (CTD). During Pol II elongation, actin is necessary to mediate the association of P-TEFb and elongating Pol II (Serine 2 phosphorylated CTD Pol II). Actin and hnRNP U are associated with the hyperphosphorylated form of Pol II CTD and play an important role in recruiting histone acetyltransferases (HATs), which facilitate permissive chromatin states for transcription by acetylating histone H3K9. Actin also binds to hnRNP and hnRNP U on pre-mRNA. The BAF complex can associate with nascent pre-mRNP (ribonucleoprotein complexes)  and may affect chromatin remodeling for transcription. Furthermore, the PSF-NonO-N-WASP(or WASP) complex can interact with elongating Pol II. N-WASP promotes actin nucleation with the Arp2/3 complex. Polymerized actin (non-canonical actin filaments) may be readily depolymerized by cofilin to provide monomeric actin for transcriptional elongation. In fact, cofilin is exclusively associated with gene coding regions, but not with promoters . In addition, actin polymerization may help to increase a local concentration of actin near the transcription site. Pre-mRNA produced by Pol II is indicated as a yellow line and the CTD of Pol II as a red line
Fig. 3. Nuclear actin and transcriptional activation. a Serum response factor (SRF) requires MAL, its coactivator, to achieve transcription from target genes. MAL translocates to nuclei, but is exported to the cytoplasm when it binds to monomeric actin, thus preventing transcriptional activation. When cytoplasmic actin is polymerized, the monomeric actin pool is decreased and hence MAL free from actin binding is increased, thereby inducing transcription from SRF target genes. b Retinoic acid (RA) activates the RA receptor (RAR) and RAR works as a transcriptional activator on its target genes together with Prep1 and N-WASP. N-WASP may recruit polymerized actin on active genes. c Nuclear actin levels are maintained by active nuclear import and export of actin. Importin 9 imports cytoplasmic actin to nuclei, while nuclear actin is exported to the cytoplasm by Exportin 6 (Exp6). High nuclear actin levels can support active transcription. d Nuclear co-repressor (NCoR) complexes inhibit transcription from Toll-like receptor-responsive genes. NCoR complexes contain Coronin 2A, which can bind to polymerized actin. Binding of actin polymers to Coronin 2A induces dissociation of NCoR complexes from silenced genes, thereby allowing transcriptional activation
Fig. 4. A model of nuclear actin-mediated transcriptional reprogramming of occluded genes. Expression of occluded genes, such as Oct4, is repressed by chromatin-based mechanisms. During transcriptional reprogramming, repressors and/or repressive marks that restrict access of transcriptional activators to chromatin may be removed with the help of nuclear actin. In addition, actin-containing chromatin remodeling complexes like the BAF complex can accelerate chromatin opening. Clearing chromatin-based repression enables transcriptional activators and Pol II to have access to promoters of occluded genes. Pol II-mediated transcription is also enhanced by nuclear actin