Exploring the Transcription–Chromatin Interface

Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press MEETING REVIEW Exploring the transcription–chromatin interface Katherine A. Jones1,3 and James T. Kadonaga2 1Regulatory Biology Laboratory, The Salk Institute, La Jolla, California 92037 USA; 2Section of Molecular Biology and Center for Molecular Genetics, University of California, San Diego, La Jolla, California 92093-0347 USA Para lograr lo posible conviene a veces apuntar a lo imposible. (To achieve the possible, it is sometimes necessary to aim for the impossible.) Charlas de Cafe´ The control of eukaryotic transcription requires the se- family, as do two mammalian remodeling complexes, quential interaction and precise coordination of a variety RSF and hACF/WCRF (Danny Reinberg, UMDNJ). In of large enzymatic complexes that are recruited by se- contrast, SWI/SNF remodeling complexes contain quence-specific promoter/enhancer-binding proteins (Fig. ATPase subunits in the SWI2/SNF2 family. Although 1). Regulation is exerted at all levels of the process, which the SWI/SNF and ISWI remodeling factors display simi- include chromatin recognition and reconfiguration, co- lar catalytic activities in ATP-dependent nucleosome valent modification of histones, recruitment of coactiva- spacing and mobilization assays in vitro, genetic studies tors and basal transcription components, and the assem- have revealed distinct roles for these complexes in the bly of an elongation-competent transcription complex regulation of specific subsets of genes as well as in other that is capable of moving efficiently through nucleo- processes such as DNA replication and repair. somal arrays. At the Workshop, Carl Wu (NIH) described the cloning Recent years have seen an explosion of new findings of the largest subunit of the Drosophila NURF complex. concerning how transcriptional regulation is exerted This novel protein contains several motifs found in other through complex regulatory elements in the context of a chromatin remodeling proteins. Analysis of larvae with chromatin template. The Workshop on “Integration of mutations in this subunit revealed defects in gene ex- Transcriptional Regulation and Chromatin Structure,” pression, consistent with the biochemical role of NURF hosted by the Fundacio´n Juan March in Madrid, Spain, in transcription on chromatin. The recombinant, four- was organized by Juan Ausio´, Enrique Palacia´n, and Jim subunit NURF complex fully reconstitutes nucleosome Kadonaga to address some of the newest emerging remodeling functions in vitro. The Wu laboratory has themes in chromatin and transcription. Specific sessions also identified a new yeast remodeling complex, termed focused on the functions of specialized core promoter the INO80 complex. This multiprotein complex con- structures, promoter/enhancer-binding factors and asso- tains the INO80 ATPase, a member of the SNF2/SWI2 ciated coregulators, chromatin remodeling and modifi- superfamily. The INO80 complex appears to be required cation complexes, as well as boundary elements and lo- for transcription of a subset of genes as well as for DNA cus control regions. recombination or repair. New findings presented by Pierre Chambon (IGBMC, Strasbourg, France) revealed that ligand-dependent acti- ATP-dependent chromatin remodeling complexes vation of the RAR␣/RXR␣ heterodimer in vitro requires One of the earliest steps of gene activation involves the the action of both ISWI and SWI/SNF chromatin remod- mobilization of energy-dependent chromatin remodeling eling complexes as well as histone acetyltransferase complexes. A variety of different complexes capable of complexes (p300 and TIF2). The ISWI remodeling com- assembling and disrupting nucleosome arrays have been plexes appeared to function before the acetyltransferases identified from yeast, Drosophila, and mammalian cells. and act in part to facilitate tight binding of the nuclear In general, these complexes are classified according to receptor heterodimer to chromatin. Studies with the the identity of the catalytic ATPase and other shared MMTV promoter demonstrated that chromatin remod- subunits. For example, the Drosophila ACF, NURF, and eling can also contribute to the synergistic effect of mul- CHRAC complexes use ATPase subunits in the ISWI tiple promoter/enhancer factors, as remodeling complexes recruited by hormone receptors allowed subse- 3Corresponding author. quent binding of NF1, which in turns stabilizes an open E-MAIL [email protected]; FAX (858) 535-8194. nucleosome complex and facilitates the binding of addi- 1992 GENES & DEVELOPMENT 14:1992–1996 © 2000 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/00 $5.00; www.genesdev.org Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press New dimensions in chromatin and transcription Figure 1. Regulation of transcription by RNA polymerase II. In this model, the initial step in transcription activation involves the recognition of the promoter/enhancer region by sequence-specific DNA-binding factors. These factors recruit ATP-using chromatin remodeling factors to the template. In some cases, sequence-specific DNA-binding factors and remodeling factors may bind to chromatin in a concerted fashion. Chromatin-remodeling factors catalyze the mobilization of nucleosomes, as is needed for the binding of additional transcription factors and coregulators to the DNA template. In addition, the promoter/enhancer-binding factors mediate, directly or indirectly, the association of acetyltransferases (such as CBP/p300, PCAF/Gcn5, SRC/p160) that modify core histones and other proteins essential for transcription initiation. Protein acetylation probably acts through multiple mechanisms to promote unfolding of the chromatin, to modulate the affinity of DNA-binding factors, and to regulate activities of transcription factors and cofactors. Promoter/enhancer-binding factors also interact with a large multisubunit complex, which has related forms known as TRAP, ARC, DRIP, SMCC, NAT, SRB, and Mediator. In turn, this complex interacts with RNA polymerase II to facilitate communication with the basal transcriptional machinery. There are also direct interactions between the TAF subunits (TBP-associated factors) of the TFIID complex and promoter/enhancer-binding factors. Many, and possibly all, of these interactions are required to achieve productive transcription initiation. Transcriptional elongation through chromatin requires the action of the P-TEFb (CycT– Cdk9) and FACT (Spt16–SSRP1) complexes, and is marked by the processive phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II. Core promoter elements, such as the TATA box and DPE, can be important for enhancer-to-core promoter communication. Boundary/insulator elements demarcate domains of gene activity. Many of these activation steps can be blocked by specific repressors to prevent inappropriate gene expression or dampen the response to inducers (not shown). The fortuitous placement of heterochromatin near a euchromatic gene can have a repressive effect on transcription (position-effect variegation). tional hormone receptors (Miguel Beato, Instituto fur scription activation and remodeling can be achieved in Molecularbiologie und Tumorforschung, Marburg). vitro with only two recombinant SWI/SNF subunits. Chromatin remodeling at the yeast PHO5 and PHO8 promoters was found to require both the activation and Chromatin modification complexes and other DNA-binding domains of Pho4 (Wolfram Ho¨ rz, Univer- coregulators sity of Munich, Germany). PHO8, in contrast to PHO5, requires, in addition, chromatin remodeling and acetyl- Juan Ausio´ (University of Victoria, British Columbia, transferase complexes acting at a step subsequent to Canada) examined the effects of histone acetylation on binding of factors to the UAS/enhancer. Although acti- chromatin structure. Although hypo- and hyperacety- vation domains can recruit remodeling complexes, it is lated nucleosomes contact DNA similarly, the acety- the zinc finger domain of the erythroid-specific enhancer lated particle is more asymmetric and the histone tails factor EKLF that interacts with SWI/SNF (BRG1) com- adopt a higher degree of ␣-helical structure. In the ab- plexes to regulate ␤-globin transcription in vitro (Beverly sence of histone H1 the structural changes result in a Emerson, Salk Institute, California). Interestingly, the less densely packed fiber. Histones H3 and H2B in core Emerson laboratory also found that factor-specific tran- perticles can also be modified through transglutamina- GENES & DEVELOPMENT 1993 Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Jones and Kadonaga tion (Luis Franco, University of Valencia, Spain), which complexes for repression (Adrian Bird, Edinburgh, Scot- provides a sensitive probe for nucleosome structure and land). HDAC-containing corepressor complexes show possibly an additional regulatory modification in vivo. sharp differences in their ability to function over short or This decrease in chromatin compaction with histone long distances (Mike Levine, Berkeley, California). In acetylation is likely to be relevant to the effects of acet- studies of nuclear receptor repression of AP1 and NF-␬B yltransferases on transcriptional activity. activity, Keith Yamamoto (UCSF, California) demon- The TRAP complex was identified biochemically as a strated that whereas repression by TR requires histone coactivator

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