A comprehensive synthetic genetic interaction network governing yeast histone acetylation and deacetylation.

Histone acetylation and deacetylation are among the principal mechanisms by which chromatin is regulated during transcription, DNA silencing, and DNA repair. We analyzed patterns of genetic interactions uncovered during comprehensive genome-wide analyses in yeast to probe how histone acetyltransferase (HAT) and histone deacetylase (HDAC) protein complexes interact. The genetic interaction data unveil an underappreciated role of HDACs in maintaining cellular viability, and led us to show that deacetylation of the histone variant Htz1p at Lys 14 is mediated by Hda1p. Studies of the essential nucleosome acetyltransferase of H4 (NuA4) revealed acetylation-dependent protein stabilization of Yng2p, a potential nonhistone substrate of NuA4 and Rpd3C, and led to a new functional organization model for this critical complex. We also found that DNA double-stranded breaks (DSBs) result in local recruitment of the NuA4 complex, followed by an elaborate NuA4 remodeling process concomitant with Rpd3p recruitment and histone deacetylation. These new characterizations of the HDA and NuA4 complexes demonstrate how systematic analyses of genetic interactions may help illuminate the mechanisms of intricate cellular processes.

[1]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[2]  B. Turner,et al.  Essential and redundant functions of histone acetylation revealed by mutation of target lysines and loss of the Gcn5p acetyltransferase , 1998, The EMBO journal.

[3]  Huiming Ding,et al.  A Snf2 family ATPase complex required for recruitment of the histone H2A variant Htz1. , 2003, Molecular cell.

[4]  S. Jackson,et al.  Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. , 2004, Molecular cell.

[5]  Grant W. Brown,et al.  Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways , 2004, Nature Biotechnology.

[6]  D. Stillman,et al.  Multiple links between the NuA4 histone acetyltransferase complex and epigenetic control of transcription. , 2000, Molecular cell.

[7]  Stephen J. Elledge,et al.  Profiling Essential Genes in Human Mammary Cells by Multiplex RNAi Screening , 2008, Science.

[8]  Wei-Hua Wu,et al.  ATP-Driven Exchange of Histone H2AZ Variant Catalyzed by SWR1 Chromatin Remodeling Complex , 2004, Science.

[9]  Rafael A Irizarry,et al.  Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. , 2006, Molecular cell.

[10]  Song Tan,et al.  The Saccharomyces cerevisiae Piccolo NuA4 Histone Acetyltransferase Complex Requires the Enhancer of Polycomb A Domain and Chromodomain To Acetylate Nucleosomes , 2005, Molecular and Cellular Biology.

[11]  Michael Grunstein,et al.  Genome-wide patterns of histone modifications in yeast , 2006, Nature Reviews Molecular Cell Biology.

[12]  O. Aparicio,et al.  H2A.Z Functions To Regulate Progression through the Cell Cycle , 2006, Molecular and Cellular Biology.

[13]  J. Denu.  The Sir 2 family of protein deacetylases. , 2005, Current opinion in chemical biology.

[14]  Y. Doyon,et al.  Eaf1 Is the Platform for NuA4 Molecular Assembly That Evolutionarily Links Chromatin Acetylation to ATP-Dependent Exchange of Histone H2A Variants , 2008, Molecular and Cellular Biology.

[15]  B. Franklin Pugh,et al.  Genome-Wide Relationships between TAF1 and Histone Acetyltransferases in Saccharomyces cerevisiae , 2006, Molecular and Cellular Biology.

[16]  Ioannis Xenarios,et al.  Microarray Deacetylation Maps Determine Genome-Wide Functions for Yeast Histone Deacetylases , 2002, Cell.

[17]  M. Grunstein,et al.  Functions of site-specific histone acetylation and deacetylation. , 2007, Annual review of biochemistry.

[18]  M. Grunstein,et al.  TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast. , 2001, Molecular cell.

[19]  Jean-Philippe Lambert,et al.  Functional Dissection of the NuA4 Histone Acetyltransferase Reveals Its Role as a Genetic Hub and that Eaf1 Is Essential for Complex Integrity , 2008, Molecular and Cellular Biology.

[20]  J. E. Halley,et al.  Telomeric heterochromatin boundaries require NuA4-dependent acetylation of histone variant H2A.Z in Saccharomyces cerevisiae. , 2006, Genes & development.

[21]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[22]  M. Grunstein,et al.  HDA1 and HDA3 Are Components of a Yeast Histone Deacetylase (HDA) Complex* , 1996, The Journal of Biological Chemistry.

[23]  Grant W. Brown,et al.  Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map , 2007, Nature.

[24]  Sean R. Collins,et al.  Exploration of the Function and Organization of the Yeast Early Secretory Pathway through an Epistatic Miniarray Profile , 2005, Cell.

[25]  M. L. Watson.  THE NUCLEAR ENVELOPE: ITS STRUCTURE AND RELATION TO CYTOPLASMIC MEMBRANES , 1955 .

[26]  N. Krogan,et al.  The Saccharomyces cerevisiae histone H2A variant Htz1 is acetylated by NuA4. , 2006, Genes & development.

[27]  Song Tan,et al.  Yeast enhancer of polycomb defines global Esa1-dependent acetylation of chromatin. , 2003, Genes & development.

[28]  B. Pugh,et al.  A genome-wide housekeeping role for TFIID and a highly regulated stress-related role for SAGA in Saccharomyces cerevisiae. , 2004, Molecular cell.

[29]  G. Cagney,et al.  Proteasome involvement in the repair of DNA double-strand breaks. , 2004, Molecular cell.

[30]  Bing Li,et al.  Histone H3 Methylation by Set2 Directs Deacetylation of Coding Regions by Rpd3S to Suppress Spurious Intragenic Transcription , 2005, Cell.

[31]  Huiming Ding,et al.  The synthetic genetic interaction spectrum of essential genes , 2005, Nature Genetics.

[32]  B. Cairns,et al.  The Yaf9 Component of the SWR1 and NuA4 Complexes Is Required for Proper Gene Expression, Histone H4 Acetylation, and Htz1 Replacement near Telomeres , 2004, Molecular and Cellular Biology.

[33]  M. Grunstein,et al.  Yeast HOS3 forms a novel trichostatin A-insensitive homodimer with intrinsic histone deacetylase activity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  P. Marks,et al.  Histone deacetylase inhibitors: molecular mechanisms of action , 2007, Oncogene.

[35]  G. Church,et al.  Modular epistasis in yeast metabolism , 2005, Nature Genetics.

[36]  S. Gasser,et al.  The nuclear envelope and transcriptional control , 2007, Nature Reviews Genetics.

[37]  P. Grant,et al.  NuA4, an essential transcription adaptor/histone H4 acetyltransferase complex containing Esa1p and the ATM‐related cofactor Tra1p , 1999, The EMBO journal.

[38]  C. Allis,et al.  ESA1 is a histone acetyltransferase that is essential for growth in yeast. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Kron,et al.  NuA4 Subunit Yng2 Function in Intra-S-Phase DNA Damage Response , 2002, Molecular and Cellular Biology.

[40]  B. Garvik,et al.  Principles for the buffering of genetic variation. , 2001 .

[41]  J. Boeke,et al.  Plasmid-chromosome shuffling for non-deletion alleles in yeast , 2008, Nature Methods.

[42]  Jacques Côté,et al.  The highly conserved and multifunctional NuA4 HAT complex. , 2004, Current opinion in genetics & development.

[43]  Tatyana Kalashnikova,et al.  Histone H2A.Z Regulates Transcription and Is Partially Redundant with Nucleosome Remodeling Complexes , 2000, Cell.

[44]  L. Aravind,et al.  Role of Rpn11 Metalloprotease in Deubiquitination and Degradation by the 26S Proteasome , 2002, Science.

[45]  Michael Grunstein,et al.  Global histone acetylation and deacetylation in yeast , 2000, Nature.

[46]  J. Tyler,et al.  Localized Histone Acetylation and Deacetylation Triggered by the Homologous Recombination Pathway of Double-Strand DNA Repair , 2005, Molecular and Cellular Biology.

[47]  E. Seto,et al.  Histone deacetylases and cancer , 2007, Oncogene.

[48]  Nevan J. Krogan,et al.  Cotranscriptional Set2 Methylation of Histone H3 Lysine 36 Recruits a Repressive Rpd3 Complex , 2005, Cell.

[49]  Bing Li,et al.  Combined Action of PHD and Chromo Domains Directs the Rpd3S HDAC to Transcribed Chromatin , 2007, Science.

[50]  J. Haber,et al.  Saccharomyces Ku70, Mre11/Rad50, and RPA Proteins Regulate Adaptation to G2/M Arrest after DNA Damage , 1998, Cell.

[51]  M. Osley,et al.  Chromatin remodelling at a DNA double-strand break site in Saccharomyces cerevisiae , 2005, Nature.

[52]  Jerry L. Workman,et al.  Histone acetyltransferase complexes: one size doesn't fit all , 2007, Nature Reviews Molecular Cell Biology.

[53]  M. Grunstein,et al.  Acetylation of H2AZ Lys 14 is associated with genome-wide gene activity in yeast. , 2006, Genes & development.

[54]  T. Hughes,et al.  Regulation of chromosome stability by the histone H2A variant Htz1, the Swr1 chromatin remodeling complex, and the histone acetyltransferase NuA4. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Hiten D. Madhani,et al.  Conserved Histone Variant H2A.Z Protects Euchromatin from the Ectopic Spread of Silent Heterochromatin , 2003, Cell.

[56]  Alexander W. Bird,et al.  Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair , 2002, Nature.

[57]  P. Grant,et al.  Histone H3 specific acetyltransferases are essential for cell cycle progression. , 2001, Genes & development.

[58]  P. Rahl,et al.  Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation. , 2005, Molecular cell.

[59]  Andrew J Link,et al.  A Protein Complex Containing the Conserved Swi2/Snf2-Related ATPase Swr1p Deposits Histone Variant H2A.Z into Euchromatin , 2004, PLoS biology.

[60]  L. Pillus,et al.  Esa1p Is an Essential Histone Acetyltransferase Required for Cell Cycle Progression , 1999, Molecular and Cellular Biology.

[61]  R. Courbeyrette,et al.  Yaf9, a Novel NuA4 Histone Acetyltransferase Subunit, Is Required for the Cellular Response to Spindle Stress in Yeast , 2003, Molecular and Cellular Biology.

[62]  Gary D Bader,et al.  Global Mapping of the Yeast Genetic Interaction Network , 2004, Science.