Genome-wide Analysis Reveals MOF as a Key Regulator of Dosage Compensation and Gene Expression in Drosophila

Dosage compensation, mediated by the MSL complex, regulates X-chromosomal gene expression in Drosophila. Here we report that the histone H4 lysine 16 (H4K16) specific histone acetyltransferase MOF displays differential binding behavior depending on whether the target gene is located on the X chromosome versus the autosomes. More specifically, on the male X chromosome, where MSL1 and MSL3 are preferentially associated with the 3' end of dosage compensated genes, MOF displays a bimodal distribution binding to promoters and the 3' ends of genes. In contrast, on MSL1/MSL3 independent X-linked genes and autosomal genes in males and females, MOF binds primarily to promoters. Binding of MOF to autosomes is functional, as H4K16 acetylation and the transcription levels of a number of genes are affected upon MOF depletion. Therefore, MOF is not only involved in the onset of dosage compensation, but also acts as a regulator of gene expression in the Drosophila genome.

[1]  Helen E. Parkinson,et al.  ArrayExpress—a public database of microarray experiments and gene expression profiles , 2006, Nucleic Acids Res..

[2]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[3]  Saeed Tavazoie,et al.  Mapping Global Histone Acetylation Patterns to Gene Expression , 2004, Cell.

[4]  G. Gilfillan,et al.  Targeting Determinants of Dosage Compensation in Drosophila , 2006, PLoS genetics.

[5]  Michael Snyder,et al.  ChIP-chip: a genomic approach for identifying transcription factor binding sites. , 2002, Methods in enzymology.

[6]  M. Pazin,et al.  Histone H4-K16 Acetylation Controls Chromatin Structure and Protein Interactions , 2006, Science.

[7]  D. Schübeler,et al.  Transcription-Coupled Methylation of Histone H3 at Lysine 36 Regulates Dosage Compensation by Enhancing Recruitment of the MSL Complex in Drosophila melanogaster , 2008, Molecular and Cellular Biology.

[8]  Xing Wang Deng,et al.  Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. , 2006, Molecular cell.

[9]  B. Morgan,et al.  Genetic analysis of histone H4: essential role of lysines subject to reversible acetylation. , 1990, Science.

[10]  J. Martens,et al.  Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. , 2003, Molecular cell.

[11]  C. Worby,et al.  RNA Interference of Gene Expression (RNAi) in Cultured Drosophila Cells , 2001, Science's STKE.

[12]  J. Ausió,et al.  Long-range histone acetylation: biological significance, structural implications, and mechanisms. , 2006, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[13]  M. Kuroda,et al.  Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila. , 1994, Genes & development.

[14]  J. Lucchesi,et al.  mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila , 1997, The EMBO journal.

[15]  Peter J Park,et al.  High-resolution ChIP-chip analysis reveals that the Drosophila MSL complex selectively identifies active genes on the male X chromosome. , 2006, Genes & development.

[16]  W. G. Kelly,et al.  Chromatin remodeling in dosage compensation. , 2005, Annual review of genetics.

[17]  J. Birchler,et al.  Role of the male specific lethal (msl) genes in modifying the effects of sex chromosomal dosage in Drosophila. , 1999, Genetics.

[18]  A. Shevchenko,et al.  Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. , 1996, Analytical chemistry.

[19]  M. Grunstein,et al.  Genetic evidence for an interaction between SIR3 and histone H4 in the repression of the silent mating loci in Saccharomyces cerevisiae. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Tamkun,et al.  Modulation of ISWI function by site‐specific histone acetylation , 2002, EMBO reports.

[21]  M. Hentze,et al.  Sex-lethal imparts a sex-specific function to UNR by recruiting it to the msl-2 mRNA 3' UTR: translational repression for dosage compensation. , 2006, Genes & development.

[22]  C. Allis,et al.  Linking Global Histone Acetylation to the Transcription Enhancement of X-chromosomal Genes in Drosophila Males* , 2001, The Journal of Biological Chemistry.

[23]  B M Turner,et al.  Identification of a conserved erythroid specific domain of histone acetylation across the α-globin gene cluster , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Lichter,et al.  hMOF Histone Acetyltransferase Is Required for Histone H4 Lysine 16 Acetylation in Mammalian Cells , 2005, Molecular and Cellular Biology.

[25]  Jop Kind,et al.  Cotranscriptional recruitment of the dosage compensation complex to X-linked target genes. , 2007, Genes & development.

[26]  T. Straub,et al.  Dosage compensation: the beginning and end of generalization , 2007, Nature Reviews Genetics.

[27]  Bing Li,et al.  MSL complex is attracted to genes marked by H3K36 trimethylation using a sequence-independent mechanism. , 2007, Molecular cell.

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

[29]  Michael Grunstein,et al.  Histone acetylation and deacetylation in yeast , 2003, Nature Reviews Molecular Cell Biology.

[30]  B. van Steensel,et al.  Chromosome-wide gene-specific targeting of the Drosophila dosage compensation complex. , 2006, Genes & development.

[31]  A. Akhtar,et al.  The right dose for every sex , 2006, Chromosoma.

[32]  Thomas A. Milne,et al.  WDR5 Associates with Histone H3 Methylated at K4 and Is Essential for H3 K4 Methylation and Vertebrate Development , 2005, Cell.

[33]  V. Solovyev,et al.  Expression of Msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila , 1995, Cell.

[34]  R. Kelley,et al.  Extent of Chromatin Spreading Determined by roX RNA Recruitment of MSL Proteins , 2002, Science.

[35]  C. Allis,et al.  The Drosophila MSL Complex Acetylates Histone H4 at Lysine 16, a Chromatin Modification Linked to Dosage Compensation , 2000, Molecular and Cellular Biology.

[36]  Hedi Peterson,et al.  g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments , 2007, Nucleic Acids Res..

[37]  Steven J Altschuler,et al.  Genomic characterization reveals a simple histone H4 acetylation code. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  T. Straub,et al.  Functional integration of the histone acetyltransferase MOF into the dosage compensation complex , 2004, The EMBO journal.

[39]  Ronald L. Davis,et al.  Epigenetic Spreading of the Drosophila Dosage Compensation Complex from roX RNA Genes into Flanking Chromatin , 1999, Cell.

[40]  E. Koonin,et al.  Male‐specific lethal 2, a dosage compensation gene of Drosophila, undergoes sex‐specific regulation and encodes a protein with a RING finger and a metallothionein‐like cysteine cluster. , 1995, The EMBO journal.

[41]  B. S. Baker,et al.  The msl-2 dosage compensation gene of Drosophila encodes a putative DNA-binding protein whose expression is sex specifically regulated by Sex-lethal. , 1995, Development.

[42]  P. Becker,et al.  Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. , 2000, Molecular cell.

[43]  E. Seto,et al.  HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention , 2007, Oncogene.

[44]  William Arbuthnot Sir Lane,et al.  A Human Protein Complex Homologous to the Drosophila MSL Complex Is Responsible for the Majority of Histone H4 Acetylation at Lysine 16 , 2005, Molecular and Cellular Biology.

[45]  D. Schübeler.  Dosage compensation in high resolution: global up-regulation through local recruitment. , 2006, Genes & development.

[46]  M. Lercher,et al.  X-chromosome-wide profiling of MSL-1 distribution and dosage compensation in Drosophila. , 2006, Genes & development.

[47]  Thomas A. Milne,et al.  Physical Association and Coordinate Function of the H3 K4 Methyltransferase MLL1 and the H4 K16 Acetyltransferase MOF , 2005, Cell.

[48]  I. Marín.  Evolution of Chromatin-Remodeling Complexes: Comparative Genomics Reveals the Ancient Origin of “Novel” Compensasome Genes , 2003, Journal of Molecular Evolution.

[49]  Rafael A. Irizarry,et al.  A Model-Based Background Adjustment for Oligonucleotide Expression Arrays , 2004 .

[50]  Malgorzata Schelder,et al.  Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. , 2006, Molecular cell.

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