Nuclear Actin-Related Proteins as Epigenetic Regulators of Development (original) (raw)
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Nuclear Actin-Related Proteins as Epigenetic Regulators of Development1
2000
Complex regulatory networks control cell fate and the development of organs and tissues in multicellular organisms. But what mechanisms initiate the neces- sary global changes in patterns of gene expression? What regulates the regulators of organismal develop- ment? The nuclear actin-related proteins (ARPs) par- ticipate in macromolecular chromatin-remodeling machines that regulate the transcription of develop- mentally important genes. In Arabidopsis
Nuclear actin and actin-binding proteins in the regulation of transcription and gene expression
FEBS Journal, 2009
Nuclear actin is involoved in transcription of all three RNA polymerases, chromatin remodeling, and formation of hnRNP complexes as well as recruitment of histone modifier to the active gene. In addition, actin-binding proteins (ABPs) control actin nucleation, bundling, filament capping, fragmentation, and monomer availability in the cytoplasm. In recent years, more and more attention is on the role of actin and ABPs in the modulation of the subcellular localization of transcriptional regulators. This review focuses on the recent developments about transcription and transcriptional regulation by nuclear actin, regulation of muscle-specific gene expression, nuclear receptor and transcription complexes by ABPs. Among them, STARS and ABLIM regulate actin dynamics and SRF-dependent muscle-specific gene expression. Functionally and structurally unrelated cytoplasmic ABPs interact cooperatively with nuclear receptor and regulate its transactivation. Furthermore, ABPs also participate in the formation of transcription complexes.
Nuclear actin levels as an important transcriptional switch
Transcription
Nuclear actin levels have recently been linked to different cellular fates, suggesting that actin could act as a switch between altered transcriptional states. Here we discuss our latest results on the mechanisms by which nuclear actin levels are regulated and their implications to the functional significance of nuclear actin.
New Insights into Cellular Functions of Nuclear Actin
Biology
Actin is one of the most abundant proteins in eukaryotic cells. There are different pools of nuclear actin often undetectable by conventional staining and commercial antibodies used to identify cytoplasmic actin. With the development of more sophisticated imaging and analytical techniques, it became clear that nuclear actin plays a crucial role in shaping the chromatin, genomic, and epigenetic landscape, transcriptional regulation, and DNA repair. This multifaceted role of nuclear actin is not only important for the function of the individual cell but also for the establishment of cell fate, and tissue and organ differentiation during development. Moreover, the changes in the nuclear, chromatin, and genomic architecture are preamble to various diseases. Here, we discuss some of the newly described functions of nuclear actin.
Analysis of nuclear actin-interacting proteins and actin-regulated transcription factors
2019
Actin is best-known from its functions in the cytoplasm, where it is a key component of the cytoskeleton. Cytoskeleton is vital for cells as it enables cell movement and maintains cell shape. Nevertheless, functions of actin are not restricted to the cytoplasm, since actin is also present in the nucleus, where it has been linked to multiple functions from gene activation to chromatin remodeling. Live cell imaging with different nuclear actin probes have demonstrated the importance of actin dynamics inside the nucleus, but the molecular mechanisms by which actin operates in the nucleus are still poorly understood. This is mainly because of the lack of wellcharacterized binding partners for nuclear actin. Therefore, the aim of this thesis was to identify and characterize novel nuclear actin-binding partners and elucidate the molecular mechanisms behind actin regulated transcription factors. To identify nuclear actin-binding partners, we used two complementary mass spectrometry (MS) techniques, affinity purification combined with MS (AP-MS) and proximity dependent biotin identification with MS (BioID). AP-MS protocol was optimized to preserve complete nuclear complexes and BioID was geared towards identifying more transient interactions. We utilized different actin constructs to discriminate nuclear versus cytoplasmic interactions and to assess the requirement for actin polymerization for the putative nuclear interactions. Analysis of our interactome data revealed that actin can form stable complexes with proteins related to chromatin remodeling but seems to function in a dynamic fashion in other nuclear processes, such as transcription and DNA replication. In our experimental setup actin seemed to be monomeric when it associated with nuclear complexes. We also discovered a novel actin-containing complex, human Ada-Two-A-containing complex (hATAC). HATAC is a histone modifying complex and further studies showed that actin directly binds one of it subunits, lysine acetyltransferase 14 (KAT14). We showed that actin-binding modulates histone acetyl transferase (HAT) activity of KAT14 in vitro and in cells. We obtained numerous RNA splicing and mRNA processing factors with our BioID approach, which led us to investigate the role of actin in RNA splicing. Bimolecular fluorescent complementation (BiFC) assays demonstrated that actin associates with different splicing factors and we further showed, for the first time, that actin has a functional role in mRNA splicing, as alterations in nuclear actin levels disturbed survival motor neuron protein 2 (SMN2) alternative exon skipping. In addition, the nuclear actin interactome analysis provided new insights into nuclear processes already earlier linked to actin, such as chromatin remodeling, transcription and DNA replication, and hence this work provides a protein interaction platform for further mechanistic studies of nuclear actin-dependent functions. This thesis work has thereby broadened the knowledge of nuclear actin-binding partners as well as revealed novel regulatory properties of actin-regulated RPEL domain containing proteins.
Nuclear Actin-Binding Proteins as Modulators of Gene Transcription
Traffic, 2005
Dynamic transformations in the organization of the cellular microfilament system are the driving force behind fundamental biological processes such as cellular motility, cytokinesis, wound healing and secretion. Eukaryotic cells express a plethora of actin-binding proteins (ABPs) allowing cells to control the organization of the actin cytoskeleton in a flexible manner. These structural proteins were, not surprisingly, originally described as (major) constituents of the cytoplasm. However, in recent years, there has been a steady flow of reports detailing not only translocation of ABPs into and out of the nucleus but also describing their role in the nuclear compartment. This review focuses on recent developments pertaining to nucleocytoplasmic transport of ABPs, including their mode of translocation and nuclear function. In particular, evidence that structurally and functionally unrelated cytoplasmic ABPs regulate transcription activation by various nuclear (steroid hormone) receptors is steadily accruing. Furthermore, the recent finding that actin is a necessary component of the RNA polymerase II-containing preinitiation complex opens up new opportunities for nuclear ABPs in gene transcription regulation.
Role of Actin Dependent Nuclear Deformation in Regulating Early Gene Expression
PLoS ONE, 2012
The nucleus of a living cell is constantly undergoing changes in shape and size as a result of various mechanical forces in physiology. These changes correlate with alterations in gene expression, however it is unclear whether nuclear deformation alone is sufficient to elicit these alterations. We used T-cell activation as a model system to test the coupling between nuclear deformation (elongation) and gene expression. Naïve T-cell activation with surrogate antigens resulted in actin dependent nuclear elongation. This was accompanied with Erk and NF-kB signaling to the nucleus to induce CD69 expression. Importantly, inhibiting actin polymerization abolished both nuclear elongation and CD69 expression, while inhibiting Erk, NF-kB or microtubule depolymerization only abolished expression but not elongation. Immobilization of antigen-coated beads, under conditions where actin polymerization was inhibited, rescued both nuclear elongation and CD69 expression. In addition, fibroblast cells plated on fibronectin micropatterns of different sizes showed correlation between nuclear shape index and tenascin C expression. Upon inhibiting the signaling intermediate Erk, tenascin C expression was down regulated although the nuclear shape index remained unaltered. Our results highlight the importance of specific signaling intermediates accompanied with nuclear deformation in the modulation of cellular genomic programs.
Actin-related proteins in the nucleus: life beyond chromatin remodelers
Current Opinion in Cell Biology, 2010
Since their discovery in the mid-1990s, nuclear actin-related proteins (ARPs) have gained attention for their roles as structural components of ATP-dependent chromatinremodeling complexes. These remodelers can move nucleosomes along the DNA, evict them from chromatin, and exchange histone variants to alter chromatin states locally. Chromatin-remodeling facilitates DNA-templated processes such as transcription regulation, DNA replication, and repair. Consistent with a role for ARPs in shaping chromatin structure, recent genetic studies show that they affect developmental and cell-type specific transcriptional programming. Here, we focus on recent results that suggest a specific contribution of ARPs to long-range interactions in the nucleus, and review evidence indicating that some ARPs may act independently of chromatin-remodeling machines.
Gene, 2001
Actin-related proteins (Arps), which share a basal structure with actin isoforms but possess different functions, have been identi®ed in a wide variety of organisms. The Arps are classi®ed into subfamilies based on the relatedness of their sequences and functions. Recently, several Arp subfamilies have been shown to be localized in the nucleus and included in protein complexes involved in the organization of chromatin structure, for example, in chromatin remodeling and histone acetyltransferase complexes. A member of the Arp6 subfamily in Drosophila, dArp6, is localized on centric heterochromatin together with heterochromatin protein 1 (HP1). We have identi®ed the ®rst examples of the Arp6 subfamily in vertebrates, novel human and chicken Arps, hArp6 and gArp6, respectively. They are closely related to each other (98% similar) and show apparent similarity to dArp6 (70%). In addition, the hArp6 gene possesses evolutionarily conserved exon/ intron structures compared with genes for members of the Arp6 subfamily in invertebrates. Like Drosophila dArp6, gArp6 is expressed abundantly in the early developmental stages, when heterochromatin condensation and nuclear maturation occur. The ®nding of a conserved Arp6 subfamily in vertebrates will contribute to the understanding of molecular mechanisms of heterochromatin organization.