Elsevier

Gene

Volume 236, Issue 2, 20 August 1999, Pages 197-208
Gene

Review
Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key?

https://doi.org/10.1016/S0378-1119(99)00261-9Get rights and content

Abstract

The transcription factor YY1 is a complex protein that is involved in repressing and activating a diverse number of promoters. Numerous studies have attempted to understand how this one factor can act both as a repressor and an activator in such a wide set of different contexts. The fact that YY1 interacts with a number of key regulatory proteins (e.g. TBP, TFIIB, TAFII55, Sp1, and E1A) has suggested that these interactions are important for determining which particular function of YY1 is displayed at a specific promoter. Two groups of proteins, previously known to function as corepressors and coactivators, that now seem likely to modulate YY1's functions, are the histone deacetylases (HDAC) and histone acetyltransferases (HAT). These two groups of enzymes modify histones, and this modification is proposed to alter chromatin structure. Acetylated histones are typically localized to active chromatin while deacetylated histones colocalize with transcriptionally inactive chromatin. When these enzymes are directed to a promoter through a DNA binding factor such as YY1, that promoter can be activated or repressed. This review will discuss the recent work dealing with the different proteins that interact with YY1, with particular emphasis on ones that modify chromatin, and how they could be involved in regulating YY1's activities.

Introduction

Transcriptional activation and repression of a given gene are critical for its proper regulation. Early models of eukaryotic transcriptional regulation often portray a trans-activator or trans-repressor interacting with the general transcription factors or with each other to regulate their respective target genes. Over the years, however, we have learned that the mechanisms of activation and repression are far more complicated. For example, we have begun to appreciate that many accessory factors, known as coactivators and corepressors, are required for most activators and repressors to function properly. Another layer of complexity was recently added to the understanding of transcriptional regulation when it was discovered that some of these cofactors contain catalytic activities that can modify histones. Specifically, some coactivators have been found to contain histone acetyltransferase (HAT) activities while some corepressors contain histone deacetylase (HDAC) activities. This intriguing discovery is important because the structure of chromatin can be modulated by the post-translational modification of histones (Grunstein, 1997, Roth and Allis, 1996, Wade et al., 1997). The acetylation state of histone tails affects their affinity with DNA in vitro (Hong et al., 1993). In addition, acetylated histones destabilize higher-order folding of chromatin (Hansen et al., 1998). Hyperacetylation of histones is believed to cause the chromatin to be more accessible for interaction with DNA binding proteins (Bauer et al., 1994, Garcia-Ramirez et al., 1995, Norton et al., 1989). Consistent with this view is the observation that histones localized to transcriptionally active chromatin typically have a higher level of acetylation compared with histones localized to inactive chromatin (Struhl, 1998, Wade et al., 1997).

The focus of this review is the transcription factor Yin Yang 1 [YY1 (also known as δ, NF-E1, UCRBP, and CF1)] that may use HAT and HDAC cofactors to exert its transcriptional functions. YY1 is a 65 kDa member of the GLI-krüppel family of zinc finger transcription factors. The expression of YY1 is ubiquitous and the protein is highly conserved among human, mouse and Xenopus (Shi et al., 1997). In Drosophila, a sequence-specific DNA binding protein, PHO (a member of the polycomb group proteins), contains a remarkable 112 out of 118 amino acid identity with YY1 over the region encoding the zinc fingers (Brown et al., 1998). However, no other region of similarity exists between PHO and YY1 outside the zinc fingers. A recent survey on the number of promoters that contain potential YY1 binding sites is overwhelming, and reports on the number of promoters that can be regulated by YY1 are equally stunning. Some examples include, but are in no way limited to, c-Myc, c-Fos, p53, α-actin, surf-2, grp78, IgH enhancer, β-casein, Igκ 3′ enhancer, ρ-globin, ε-globin, IFN-γ, rpL30, rpL32, P5 of AAV, E6 and E7 of HPV, BZLF1 of EBV, P6 of B19-parvovirus, VP5 of HSV-1, and a number of other viral LTRs (Hyde-DeRuyscher et al., 1995, Shi et al., 1997, Shrivastava and Calame, 1994, Yant et al., 1995). More recently, studies suggest that YY1 is critical in the regulation of histone genes (Eliassen et al., 1998, Last et al., 1999). In addition, YY1 recognition sites have been identified as the initiator element of some promoters (Basu et al., 1993, Seto et al., 1991, Usheva and Shenk, 1994). Originally, YY1 was isolated as a repressor of the P5 promoter of AAV, as well as the MuLV LTR, and the immunoglobulin κ 3′ enhancer (Flanagan et al., 1992, Park and Atchison, 1991, Shi et al., 1991). It was also found that the adenovirus E1A protein could alter YY1's function from a repressor to a trans-activator (Shi et al., 1991). In contrast, work by other groups, around the same time, found that YY1 acted as an activator of such genes as c-Myc and rpL30 (Hariharan et al., 1991, Riggs et al., 1993). This YY1 mediated activation occurred in the absence of E1A, demonstrating that YY1 is able to activate certain promoters in the absence of viral factors. A possible explanation for the dual nature of YY1 is that the promoter context and factors already present at a promoter dictate which function of YY1 is displayed at that promoter. Alternatively, it is conceivable that the dual nature depends on the different pre-existing YY1–cofactor complexes being recruited to a promoter under different conditions.

The corepressors most relevant to understanding the mechanism of YY1 mediated repression are the mammalian members of the RPD3 family of HDACs. Three such proteins have been cloned to date and share extensive homology to the yeast global regulator RPD3 (Hassig and Schreiber, 1997, Pazin and Kadonaga, 1997, Roth and Allis, 1996). All three are known to interact with YY1 in vitro, and at least HDAC2 potentially interacts with YY1 in vivo (Yang et al., 1996, Yang et al., 1997). Two additional classes of deacetylases have recently been cloned in maize (HD2) and mouse (mHDA1 and mHDA2) that show little or no homology to the RPD3 related deacetylases (Lusser et al., 1997, Verdel and Khochbin, 1999). The in vivo function of these new deacetylases and whether they interact with YY1 is unknown at this time.

HDAC1 was first purified through the use of a deacetylase inhibitor and subsequently cloned by reverse genetics, while HDAC2 was cloned in a two-hybrid screen with YY1 as the bait (Taunton et al., 1996, Yang et al., 1996). A complete HDAC3 cDNA clone was isolated using a probe derived from an EST sequence that shares significant homology to HDAC1 and HDAC2 (Emiliani et al., 1998, Yang et al., 1997). The HDAC3 cDNA was also independently identified from PHA-activated immune cells (Dangond et al., 1998). The HDACs exist as components of multi-subunit complexes with HDAC1 and HDAC2 often isolated in the same complex, while HDAC3 exists in a distinct complex (Hassig et al., 1998, Zhang et al., 1997). The identification and cloning of members of these complexes are active areas of investigation. In the case of the HDAC1/2 complexes, a few members have been identified and include mSin3A, N-CoR, SAP18/30, RbAp46/48, CHD3/CHD4, and MeCP2 (Heinzel et al., 1997, Jones et al., 1998, Laherty et al., 1997, Laherty et al., 1998, Nan et al., 1998, Tong et al., 1998, Xue et al., 1998, Zhang et al., 1997, Zhang et al., 1998a, Zhang et al., 1998b). mSin3A and N-CoR interact with Mad and nuclear hormone receptors, respectively, which may help direct HDAC1/2 to a given promoter. In contrast, CHD3 and CHD4 are two proteins that are autoimmune antigens associated with the connective tissue disease Mi-2 dermatomyositis and are thought to contain chromatin remodeling activities. RbAp48 is a subunit of the chromatin assembly factor 1 (Tyler et al., 1996), and MeCP2 is a protein that selectively binds to methylated DNA sequences (Lewis et al., 1992).

Since YY1 can also act as an activator, it is conceivable that it may require a coactivator to function. In this regard, CBP and p300, two highly homologous proteins that serve as coactivators for many transcriptional activators (Boyes et al., 1998, Goldman et al., 1997, Kwok et al., 1994, Sartorelli et al., 1997, Yuan et al., 1996), have been shown to interact with YY1 (Austen et al., 1997b, Galvin and Shi, 1997, Lee et al., 1995a). CBP is required for activation of CREB dependent promoters, while p300 is involved in the proper function of the adenovirus E1A protein. Recently, it was shown that these two proteins are interchangeable for interactions with CREB and are thought to be functionally homologous (Lundblad et al., 1995). Interestingly, both of these proteins have been demonstrated to contain HAT activity (Ogryzko et al., 1996). This result suggests that modification of histones and chromatin may be an important mechanism of activation for factors utilizing CBP/p300 as coactivators.

With recent advances in understanding the characteristics of coactivators and corepressors, the opportunity to understand how YY1 might function through recruitment of cofactors is becoming increasingly apparent. In this review, we will present an overview of the data, much of it complex and often contradictory, that has been collected over the last eight years on YY1. We will then explore in a critical manner the recent findings concerning cofactors that interact with YY1. Finally, we will present models and potential explanations of how YY1 might activate and repress transcription. As with most reviews of this kind, due to space limitations it is impractical and quite impossible to cite all of the works pertaining to this field. For further details on YY1, therefore, the reader should consult an excellent comprehensive review by Shi et al. (1997).

Section snippets

Functional domains of YY1

As may be expected from the multi-functional nature of YY1, structural analyses of the activation and repression domains of YY1 proved to be quite complicated. A number of groups have analyzed YY1's structure/function relationships through the expression of YY1 deletion mutants in cotransfection assays with reporter constructs. Many of these studies used the DNA binding domain of Gal4 fused to YY1 to eliminate the need for an intact YY1 DNA binding domain. Results from these studies are

Protein/protein interaction domains of YY1

Unfortunately, the complexity of YY1 does not end with its functional domains. Attempts to identify YY1 domains that are responsible for protein/protein interactions have resulted in equally complicated findings. The constellation of proteins that interact with YY1 is staggering in number, and interestingly, most of the proteins that interact with YY1 are either coactivators/corepressors or transcription factors that are important in regulating a number of diverse promoters. Also, a recent

Models of YY1 mediated repression

Several proposed models of YY1 mediated repression are diagrammed in Fig. 2 [also discussed by Shi et al. (1997)]. Earlier, it was thought that YY1 acts by sterically hindering the binding of trans-activators to DNA through overlapping DNA recognition sites. A prime example of this is the α-actin promoter where the YY1 site occludes the serum response factor binding element (SRE) (Lee et al., 1992). However, numerous examples now exist where a YY1 binding site is nowhere near another trans

Models of YY1 mediated activation

Early observations that indicated YY1 could function as a transcriptional activator came from three separate studies. First, it was shown that the adenovirus E1A protein could relieve repression exerted by YY1 and further activate transcription through a YY1-binding site (Shi et al., 1991). It was thought that E1A could somehow convert YY1 from a repressor (or non-activator) to an activator. Second, soon after the cloning of YY1, it was found that YY1 could activate transcription when bound to

Conclusion

YY1 is a fascinating example of the complexity inherent in gene regulatory systems. Much of the recent work on YY1 has gone into understanding its domain structure, identifying the factors with which it interacts, and attempting to understand its mechanisms of action. As with studies on almost any biological molecule, analysis of YY1 raises many more questions than it answers. Of immediate interest is the question of whether recruitment of chromatin remodeling proteins in general, and histone

Acknowledgements

We thank Ya-Li Yao, Jennifer Westling, Wen-Ming Yang, Yang Shi, Michael Atchison, and Rosalind Jackson for helpful suggestions on the manuscript. Work related to YY1 and histone deacetylation in our laboratory is supported by grants from the National Institutes of Health and the National Science Foundation.

References (90)

  • C.A. Hassig et al.

    Histone deacetylase activity is required for full transcriptional repression by mSin3A

    Cell

    (1997)
  • L. Hong et al.

    Studies of the DNA binding properties of histone H4 amino terminus. Thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 ‘tail’ to DNA

    J. Biol. Chem.

    (1993)
  • A. Imhof et al.

    Acetylation of general transcription factors by histone acetyltransferases

    Curr. Biol.

    (1997)
  • C.J. Inouye et al.

    Relief of YY1-induced transcriptional repression by protein–protein interaction with the nucleolar phosphoprotein B23

    J. Biol. Chem.

    (1994)
  • C.D. Laherty et al.

    Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression

    Cell

    (1997)
  • C.D. Laherty et al.

    SAP30, a component of the mSin3 corepressor complex involved in N-CoR-mediated repression by specific transcription factors

    Mol. Cell

    (1998)
  • J.S. Lee et al.

    Differential interactions of the CREB/ATF family of transcription factors with p300 and adenovirus E1A

    J. Biol. Chem.

    (1996)
  • J.D. Lewis et al.

    Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA

    Cell

    (1992)
  • V.G. Norton et al.

    Histone acetylation reduces nucleosome core particle linking number change

    Cell

    (1989)
  • V.V. Ogryzko et al.

    The transcriptional coactivators p300 and CBP are histone acetyltransferases

    Cell

    (1996)
  • M.J. Pazin et al.

    What's up and down with histone deacetylation and transcription?

    Cell

    (1997)
  • S.Y. Roth et al.

    Histone acetylation and chromatin assembly: a single escort, multiple dances?

    Cell

    (1996)
  • Y. Shi et al.

    Transcriptional repression by YY1, a human GLI-Kruppel-related protein and relief of repression by adenovirus E1A protein

    Cell

    (1991)
  • Y. Shi et al.

    Everything you have ever wanted to know about Yin Yang1…

    Biochim. Biophys. Acta

    (1997)
  • D.L. Swope et al.

    CREB-binding protein activates transcription through multiple domains

    J. Biol. Chem.

    (1996)
  • A. Usheva et al.

    TATA-binding protein-independent initiation: YY1, TFIIB and RNA polymerase II direct basal transcription on supercoiled template DNA

    Cell

    (1994)
  • A. Verdel et al.

    Identification of a new family of higher eukaryotic histone deacetylases

    J. Biol. Chem.

    (1999)
  • P.A. Wade et al.

    Histone acetylation: chromatin in action

    Trends Biochem. Sci.

    (1997)
  • Y. Xue et al.

    NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities

    Mol. Cell

    (1998)
  • W.M. Yang et al.

    Cyclophilin A and FKBP12 interact with YY1 and alter its transcriptional activity

    J. Biol. Chem.

    (1995)
  • W.M. Yang et al.

    Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family

    J. Biol. Chem.

    (1997)
  • W. Yuan et al.

    Human p300 protein is a coactivator for the transcription factor MyoD

    J. Biol. Chem.

    (1996)
  • Y. Zhang et al.

    Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex

    Cell

    (1997)
  • Y. Zhang et al.

    The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities

    Cell

    (1998)
  • Y. Zhang et al.

    SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex

    Mol. Cell

    (1998)
  • M. Austen et al.

    Regulation of cell growth by the Myc–Max–Mad network: role of Mad proteins and YY1

    Curr. Top. Microbiol. Immunol.

    (1997)
  • M. Austen et al.

    YY1 can inhibit c-Myc function through a mechanism requiring DNA binding of YY1 but neither its transactivation domain nor direct interaction with c-Myc

    Oncogene

    (1998)
  • A.J. Bannister et al.

    CBP-induced stimulation of c-Fos activity is abrogated by E1A

    EMBO J.

    (1995)
  • A.J. Bannister et al.

    Stimulation of c-Jun activity by CBP: c-Jun residues Ser63/73 are required for CBP induced stimulation in vivo and CBP binding in vitro

    Oncogene

    (1995)
  • T. Bauknecht et al.

    A novel C/EBP beta-YY1 complex controls the cell-type-specific activity of the human papillomavirus type 18 upstream regulatory region

    J. Virol.

    (1996)
  • J. Boyes et al.

    Regulation of activity of the transcription factor GATA-1 by acetylation

    Nature

    (1998)
  • S.M. Bushmeyer et al.

    Identification of YY1 sequences necessary for association with the nuclear matrix and for transcriptional repression functions

    J. Cell. Biochem.

    (1998)
  • C.M. Chiang et al.

    Cloning of an intrinsic human TFIID subunit that interacts with multiple transcriptional activators

    Science

    (1995)
  • K. Eliassen et al.

    Role for a YY1-binding element in replication-dependent mouse histone gene expression

    Mol. Cell. Biol.

    (1998)
  • S. Emiliani et al.

    Characterization of a human RPD3 ortholog, HDAC3

    Proc. Natl. Acad. Sci. USA

    (1998)
  • Cited by (0)

    View full text