After chromatin is SWItched-on can it be RUSHed?
Introduction
Transcription in eukaryotic nuclei is regulated by DNA-dependent RNA polymerases I (A), II (B) and III (C). RNA polymerase II, a multisubunit protein that transcribes all protein encoding genes (Sawadogo and Sentenac, 1990, Buratowski, 1994, Tjian and Maniatis, 1994), interacts with general transcription factors, as well as tissue- and gene-specific transcription regulators. Regulatory elements for RNA polymerase transcription are located both upstream and downstream of the RNA transcription start site. These positive and negative regulatory cis elements are binding sites for sequence-specific transcription/trans-activator proteins that activate or repress transcription (Mitchell and Tjian, 1989). Many of these proteins belong to superfamilies that are comprised of evolutionarily diverse families. Glucocorticoid, estrogen and progesterone receptors are all members of the steroid receptor family that belongs to the nuclear receptor superfamily (Gronemeyer, 1991, Mangelsdorf et al., 1995). Based on structure and function, a typical member of the nuclear receptor superfamily can be divided into five or six regions denoted A–F (Gronemeyer, 1991, Mangelsdorf et al., 1995). The A/B region is the hypervariable N-terminal region which contains a transactivation domain (AF-1). Region C is centrally located and contains the highly conserved DNA-binding domain (DBD) with an invariant pattern of cysteine residues and a dimerization domain. The DBD, which directs the receptor to specific DNA sequences or hormone response elements (HREs), is characterized by two highly conserved zinc finger motifs (Freedman, 1992). Immediately adjacent to the C-terminal zinc finger motif is a short, ligand-dependent, nuclear localization domain (NLD) which encroaches on the variable hinge region (D). Region E is the ligand-binding domain (LBD) which contains a dimerization region and two transactivation domains (AF-2 and AF-2a). The LBD is the molecular on/off switch, selectively binding hormone and converting the receptor to a transcriptionally active state from an inactive state. Whereas regions C and E contain the DBD and the LBD, the signature motifs of the nuclear receptor superfamily, no function has been assigned to region F at the C-terminus.
Section snippets
Chromatin structure
In response to hormone challenge, steroid receptors become ligand-induced homodimers that bind to palindromic DNA sequences (HREs), and interact with the transcription initiation complex that contains RNA polymerase II. However, in order for transcription to occur, chromatin, which represses transcriptional activation by inhibiting access of the basic transcription machinery to the transcription start site, and by competing with gene-specific transcription factors for their respective binding
Chromatin remodeling machines
Experiments with Drosophila embryo extracts led to the identification of three multiprotein complexes, each of which contains a subunit homologous to DNA-dependent ATPases (Cairns, 1998). NURF (nucleosome remodeling factor), is a complex of four polypeptides that mediates the ATP-dependent binding of GAGA factor to several heat-shock promoters. CHRAC (chromatin accessibility complex) is a complex of five proteins that allows broad access of restriction endonucleases to chromatin templates. ACF
The SWI-SNF complex
The yeast SWI/SNF gene regulates the switch in mating-type and the switch to different carbohydrate pathways (Burns and Peterson, 1997). The 2 MDa SWI/SNF multisubunit complex is composed of at least 11 proteins and is an integral component of the yeast RNA polymerase II holoenzyme (Wilson et al., 1996, Burns and Peterson, 1997). The SWI/SNF homolog in Drosophila is known as Brahma or brm, and like the yeast protein the encoded protein contains a bromodomain and a helicase-type domain with an
RUSH
Attention has recently been focused on the RUSH family of proteins found in multicellular eukaryotes (Chilton and Hewetson, 1998). The RUSH acronym identifies the key characteristics of the protein members of the family, i.e. ING-finger motif protein cloned in odent and abbit, binds the G promoter, WI/NF-related, and cloned in uman, binds the IV-1 promoter, elicase-like. RUSH cDNAs were isolated by recognition site screening of λgt-11 cDNA expression libraries derived from rabbit
RUSH-DNA interactions
The role of RUSH proteins in chromatin remodeling has yet to be defined. Activation of the PAI-1 gene in HeLa cells and in 30A5 cells, by hHLTF (Ding et al., 1996) and P113 (Zhang et al., 1997) respectively, provides the first in vivo evidence that RUSH proteins are transcription factors. However, the suggestion that RUSH proteins mediate the ability of prolactin to increase progesterone-dependent transcription of the uteroglobin gene (Hewetson and Chilton, 1997) suggests that RUSH proteins are
Alternative splicing
The ubiquitous expression of RUSH suggests that it may regulate gene expression in numerous cell types (Robinson et al., 1997). The preferential expression of RUSH-1α by all rabbit tissues except estrous uterine endometrium and lactating mammary gland indicates that RUSH pre-mRNAs are alternatively spliced in a tissue-specific manner. McKeown (1990) has shown that changes in the ratio of the steady state levels of mRNA products vary directly with the splice rate constant, e.g. the 61-fold
Phosphorylation
Phosphorylation of transcription factors is a rapid (<30 min) and reversible method of modulating their function. Muchardt et al. (1996) demonstrated that hbrm and BRG-1 are excluded from condensed chromatin following phosphorylation. The mitotic phosphorylation of these proteins does not disrupt their association with hSNF5 but it correlates with their decreased affinity for nuclear structure. More recently, Sif et al. (1998) showed that hSWI/SNF complexes are reversibly inactivated by
Concluding remarks
An important role of chromatin is to restrict transcription factor access to DNA. Thus chromatin plays a critical role in silencing inducible genes. SWI/SNF is a well-characterized protein complex known to facilitate transcription by reorganizing chromatin. RUSH proteins are structurally related to the SWI/SNF proteins, and uniquely conserved in the regions outside the DNA-dependent ATPase domain and RING-finger domains. Complementary DNAs for these proteins were isolated by recognition site
Acknowledgements
The authors thank Dr J.C. Daniel, Jr. Eminent Scholar at Old Dominion University (Norfolk, VA) for stimulating discussions. This work was supported by NIH Grant HD29457 (to B.S.C.).
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