Update on Nuclear Actin-Related Proteins Nuclear Actin-Related Proteins as Epigenetic Regulators of Development 1

Complex regulatory networks control cell fate and the development of organs and tissues in multicellular organisms. But what mechanisms initiate the necessary global changes in patterns of gene expression? What regulates the regulators of organismal development? The nuclear actin-related proteins (ARPs) participate in macromolecular chromatin-remodeling machines that regulate the transcription of developmentally important genes. In Arabidopsis (Arabidopsis thaliana), ARP4, ARP6, and ARP7, which are predominantly localized in the nucleus, participate in the regulation of several pathways affecting cell proliferation and organ development. The diverse plant phenotypes resulting from deficiencies in these nuclear ARPs include reduced cell size or numbers, photoperiod-dependent and -independent early flowering, delayed floral senescence, altered leaf, stem, and flower organ morphology, embryo lethality, and an assortment of male and female reproductive defects. A working hypothesis emerging from these and other plant and animal data is that diverse isoforms of nuclear ARP-containing chromatin-modifying complexes exert epigenetic control over global regulators of multicellular development. In support of this hypothesis, we herein examine nuclear ARP phylogeny, the chromatin-remodeling activities of ARPcontaining complexes that lead to epigenetic control of gene expression, the expanding developmental roles assigned to several putative plant ARP-containing complexes, as well as the evidence that a large number of ARP complex isoforms may have evolved in concert with the significant demands of multicellular development. The ARPs share limited sequence identity (15%– 60%) with conventional actins, but they appear to maintain the actin fold, a nucleotide-binding pocket and hinge region that enables a conformational change in actin. Eight to 10 ancient classes of ARPs are found in most eukaryotes that have been examined, and all appear to participate in protein complexes (McKinney et al., 2002; Blessing et al., 2004; Kandasamy et al., 2004). Several of the more divergent ARPs are homologs of yeast (Saccharomyces cerevisiae) Arp4, 5, 6, and 8, which are found primarily in the nucleus. This location distinguishes the nuclear ARPs from actin or Arp2 and Arp3, which have been found in the nucleus, but are primarily concentrated in the cytoplasm. None of the nuclear ARPs are believed to form polymers such as actin microfilaments or the short filaments formed from ARP1 in the centractin complex, which contains both ARP1 and ARP10. Nuclear ARPs act as essential subunits of macromolecular machines that remodel chromatin structure, and their only demonstrated functions are within such complexes. Specifically, ARP-containing complexes are involved in nucleosome phasing and movement, histone acetylation, and exchange of histone subunit isovariants within nucleosomes. The chromatinmodifying activities of these complexes can serve the basal regulatory function of reinforcing or alleviating the nucleosomal suppression of transcription that affects most genes (Yuan et al., 2005). However, theymay also exert more precise epigenetic control over development via the particular activities of ARP-containing complexes on the transcription of a small subset of regulatory genes. The activities of nuclear ARP complexes on genes that direct global changes in cell proliferation and ontogeny of organs and tissues are the subjects of our working hypothesis and the major focus of this Update article.