Review
Transcriptional regulation of yeast phospholipid biosynthetic genes

https://doi.org/10.1016/j.bbalip.2006.05.017Get rights and content

Abstract

The last several years have been witness to significant developments in understanding transcriptional regulation of the yeast phospholipid structural genes. The response of most phospholipid structural genes to inositol is now understood on a mechanistic level. The roles of specific activators and repressors are also well established. The knowledge of specific regulatory factors that bind the promoters of phospholipid structural genes serves as a foundation for understanding the role of chromatin modification complexes. Collectively, these findings present a complex picture for transcriptional regulation of the phospholipid biosynthetic genes. The INO1 gene is an ideal example of the complexity of transcriptional control and continues to serve as a model for studying transcription in general. Furthermore, transcription of the regulatory genes is also subject to complex and essential regulation. In addition, databases resulting from a plethora of genome-wide studies have identified regulatory signals that control one of the essential phospholipid biosynthetic genes, PIS1. These databases also provide significant clues for other regulatory signals that may affect phospholipid biosynthesis. Here, we have tried to present a complete summary of the transcription factors and mechanisms that regulate the phospholipid biosynthetic genes.

Section snippets

Transcriptional regulation of INO1 expression

The de novo synthesis of phosphatidylinositol (PI) from glucose-6-phosphate requires the INO1 structural gene that encodes inositol-3-phosphate synthase (IPS) (Fig. 1) [1], [2]. IPS is responsible for the conversion of glucose-6-phosphate to inositol-3-phosphate, which is then dephosphorylated to produce inositol [3], [4]. INO1 is regulated at the level of transcription by the soluble precursors inositol and choline. INO1 is maximally expressed in the absence of inositol and choline, partially

Transcriptional regulation of PIS1 expression

The final step in the de novo synthesis of PI requires the essential PIS1 structural gene that encodes PI synthase (PIS) (Fig. 1) [76], [77], [78], [79], [80]. PIS catalyzes the formation of PI from inositol and CDP-DAG (Fig. 1) [81], [82]. Transcriptional regulation of the PIS1 gene is understudied relative to that of the other phospholipid structural genes. This is partly because its expression is not coordinated with other phospholipid biosynthetic genes in response to inositol and choline

Transcriptional regulation of de novo PC synthesis

In Saccharomyces cerevisiae, PC can be synthesized using the CDP-diacylglycerol (CDP-DAG) de novo pathway (Fig. 1). De novo synthesis requires five genes (Fig. 1). While most of these genes are also regulated in response to inositol and choline, they have not been studied to nearly the same degree as INO1. However, several other transcription factors have been defined mostly by genome-wide strategies.

Transcriptional regulation of the PC Kennedy pathway

The Kennedy pathway utilizes ethanolamine (E) and choline (C) to synthesize PC (Fig. 1) [123]. There are six structural genes in this pathway and some of them are highly regulated in response to inositol and choline. The EKI1 and CKI1 genes are required in the first steps in the Kennedy pathway. EKI1 and CKI1 encode ethanolamine kinase and choline kinase, respectively. Both genes are regulated at the transcriptional level in response to inositol and choline in a pattern similar to that of INO1

Ino2p and Ino4p

It is generally accepted that INO2 gene is auto-regulated in response to inositol and choline. Several studies show that INO2 transcript levels, INO2-lacZ and INO2-cat reporters, and Ino2p protein levels are repressed ∼12-fold in response to inositol and choline [39], [63], [127], [128], [129], [130], [131], [132], [133], [134], [135]. However, there is one study that reports constitutive expression of Ino2p protein levels in a wild type strain [17]. The reason for this discrepancy was not

Future directions

Considerable strides have been made in recent years towards understanding the mechanisms that regulate transcription of the phospholipid structural and regulatory genes. However, many new questions emerge from these developments. The regulation of INO1 transcription is remarkable in that it involves a large number of transcription factors that bind DNA and/or regulate chromatin structure. Why there is a need for so many factors remains to be answered. It will be important to determine if these

Acknowledgements

We thank members of the Lopes lab for helpful discussions and assistance with editing. We also thank Dr. George Carman (Rutgers Univ.) for his longtime support and encouragement. We are grateful to our colleague down the hall, Dr. Miriam Greenberg, for being a constant source of inspiration and to members of her lab for continuous discussions. We are also grateful for the reviewers' helpful comments. Work in the Lopes lab is supported by a grant from the National Science Foundation to J.M.L.

References (144)

  • C.L. Peterson et al.

    A functional interaction between the C-terminal domain of RNA polymerase II and the negative regulator SIN1

    Cell

    (1991)
  • M.P. Cosma et al.

    Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter

    Cell

    (1999)
  • C.L. Peterson et al.

    Promoter targeting and chromatin remodeling by SWI/SNF

    Curr. Opin. Genet. Dev.

    (2000)
  • J. Mellor et al.

    ISW1 complexes in Saccharomyces cerevisiae

    Biochim. Biophys. Acta

    (2004)
  • G.S. Han et al.

    The Saccharomyces cerevisiae lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme

    J. Biol. Chem.

    (2006)
  • K.J. Travers et al.

    Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation

    Cell

    (2000)
  • M. Schröder et al.

    ER stress and the unfolded protein response

    Mutat. Res.

    (2005)
  • C. Patil et al.

    Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals

    Curr. Opin. Cell Biol.

    (2001)
  • S.A. Jesch et al.

    Genome-wide analysis reveals inositol, not choline, as the major effector of Ino2p–Ino4p and unfolded protein response target gene expression in yeast

    J. Biol. Chem.

    (2005)
  • J.E. Cox et al.

    A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response

    Cell

    (1996)
  • C. Sidrauski et al.

    The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response

    Cell

    (1997)
  • D.L. Vaden et al.

    Lithium and valproate decrease inositol mass and increase expression of the yeast INO1 and INO2 genes for inositol biosynthesis

    J. Biol. Chem.

    (2001)
  • J.-I. Nikawa et al.

    Primary structure and disruption of the phosphatidylinositol synthase gene of Saccharomyces cerevisiae

    J. Biol. Chem.

    (1987)
  • J.-I. Nikawa et al.

    Phosphatidylinositol synthase from yeast

    Biochim. Biophys. Acta

    (1997)
  • A.S. Fischl et al.

    Phosphatidylinositol synthase from Saccharomyces cerevisiae

    J. Biol. Chem.

    (1986)
  • M.S. Anderson et al.

    Carbon source regulation of PIS1 gene expression in Saccharomyces cerevisiae involves the MCM1 gene and the two component regulatory gene, SLN1

    J. Biol. Chem.

    (1996)
  • M.E. Gardocki et al.

    Expression of the yeast PIS1 gene requires multiple regulatory elements including a Rox1p binding site

    J. Biol. Chem.

    (2003)
  • S.-H. Han et al.

    Regulation of the PIS1-encoded phosphatidylinositol synthase in Saccharomyces cerevisiae by zinc

    J. Biol. Chem.

    (2005)
  • W.M. Iwanyshyn et al.

    Regulation of phospholipid synthesis in Saccharomyces cerevisiae by zinc

    J. Biol. Chem.

    (2004)
  • L.T. Bhoite et al.

    Mutations in the Pho2 (Bas2) transcription factor that differentially affect activation with its partner proteins Bas1, Pho4, and Swi5

    J. Biol. Chem.

    (2002)
  • T.F. Donahue et al.

    Inositol mutants of Saccharomyces cerevisiae: mapping the ino1 locus and characterizing alleles of ino1, ino2 and ino4 loci

    Genetics

    (1981)
  • L.S. Klig et al.

    Isolation of the yeast INO1 gene: located on an autonomously replicating plasmid

    Proc. Natl. Acad. Sci. U. S. A.

    (1984)
  • M.R. Culbertson et al.

    Control of inositol biosynthesis in Saccharomyces cerevisiae: properties of a repressible enzyme system in extracts of wild type (Ino+) cells

    J. Bacteriol.

    (1976)
  • M. Murray et al.

    Expression of yeast INM1 encoding inositol monophosphatase is regulated by inositol, carbon source and growth stage and is decreased by lithium and valproate

    Mol. Microbiol.

    (2000)
  • J.P. Hirsch et al.

    Expression of the Saccharomyces cerevisiae inositol-1-phosphate synthase (INO1) gene is regulated by factors that affect phospholipid synthesis

    Mol. Cell. Biol.

    (1986)
  • J. Koipally et al.

    Functional characterization of the repeated UASINO element in the promoters of the INO1 and CHO2 genes of yeast

    Yeast

    (1996)
  • J.M. Lopes et al.

    Interaction of trans and cis regulatory elements in the INO1 promoter of Saccharomyces cerevisiae

    Nucleic Acids Res.

    (1991)
  • D.M. Nikoloff et al.

    The INO2 gene of Saccharomyces cerevisiae encodes a helix–loop–helix protein that is required for activation of phospholipid synthesis

    Nucleic Acids Res.

    (1992)
  • K.A. Robinson et al.

    A network of yeast basic helix–loop–helix interactions

    Nucleic Acids Res.

    (2000)
  • K.A. Robinson et al.

    Saccharomyces cerevisiae basic helix–loop–helix proteins regulate diverse biological processes

    Nucleic Acids Res.

    (2000)
  • S. Schwank et al.

    Yeast transcriptional activator INO2 interacts as an Ino2p/Ino4p basic helix–loop–helix heteromeric complex with the inositol/choline-responsive element necessary for expression of phospholipid biosynthetic genes in Saccharomyces cerevisiae

    Nucleic Acids Res.

    (1995)
  • M. Dietz et al.

    TFIIB and subunits of the SAGA complex are involved in transcriptional activation of phospholipid biosynthetic genes by the regulatory protein Ino2 in the yeast Saccharomyces cerevisiae

    Mol. Microbiol.

    (2003)
  • J.H. Brickner et al.

    Gene recruitment of the activated INO1 locus to the nuclear membrane

    PLoS Biol.

    (2004)
  • M.K. Shirra et al.

    Inhibition of acetyl coenzyme A carboxylase activity restores expression of the INO1 gene in a snf1 mutant strain of Saccharomyces cerevisiae

    Mol. Cell. Biol.

    (2001)
  • M.K. Shirra et al.

    The Snf1 protein kinase and Sit4 protein phosphatase have opposing functions in regulating TATA-binding protein association with the Saccharomyces cerevisiae INO1 promoter

    Genetics

    (2005)
  • W.-S. Lo et al.

    Snf1-a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription

    Science

    (2001)
  • W.S. Lo et al.

    Histone H3 phosphorylation can promoter TBP recruitment through distinct promoter-specific mechanisms

    EMBO J.

    (2005)
  • M.L. Greenberg et al.

    Regulatory mutations of inositol biosynthesis in yeast: isolation of inositol-excreting mutants

    Genetics

    (1982)
  • S. Kagiwada et al.

    Role of the yeast VAP homolog, Scs2p, in INO1 expression and phospholipid metabolism

    J. Biochem.

    (2003)
  • C.J.R. Loewen et al.

    Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid

    Science

    (2004)
  • Cited by (66)

    • Phosphatidate-mediated regulation of lipid synthesis at the nuclear/endoplasmic reticulum membrane

      2020, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
    • The response to inositol: Regulation of glycerolipid metabolism and stress response signaling in yeast

      2014, Chemistry and Physics of Lipids
      Citation Excerpt :

      The cellular consequences of inositol depletion have also been studied in mammalian cells and compared to yeast in the context of exposure to inositol depleting drugs lithium and valproic acid (Deranieh and Greenberg, 2009). Various aspects of regulation and signaling related to lipid and inositol metabolism in yeast have been extensively reviewed (Carman and Han, 2011; Carman and Henry, 1999; Chen et al., 2007; Dickson, 2008; Gaspar et al., 2007; Greenberg and Lopes, 1996; Henneberry and Sturley, 2005; Henry et al., 2012; Jesch and Henry, 2005; Majerus and York, 2009; Strahl and Thorner, 2007; Tsui and York, 2010). Thus it is not the intention of this article to provide a comprehensive coverage of the broader topics of lipid and inositol metabolism in regulation and signaling in eukaryotic cells in general.

    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text