Mass Spectrometric Studies on Epigenetic Interaction Networks in Cell Differentiation*

Arrest of cell differentiation is one of the leading causes of leukemia and other cancers. Induction of cell differentiation using pharmaceutical agents has been clinically attempted for the treatment of these cancers. Epigenetic regulation may be one of the underlying molecular mechanisms controlling cell proliferation or differentiation. Here, we report on the use of proteomics-based differential protein expression analysis in conjunction with quantification of histone modifications to decipher the interconnections among epigenetic modifications, their modifying enzymes or mediators, and changes in the associated pathways/networks that occur during cell differentiation. During phorbol-12-myristate 13-acetate-induced differentiation of U937 cells, fatty acid synthesis and its metabolic processing, the clathrin-coated pit endocytosis pathway, and the ubiquitin/26 S proteasome degradation pathways were up-regulated. In addition, global histone H3/H4 acetylation and H2B ubiquitination were down-regulated concomitantly with impaired chromatin remodeling machinery, RNA polymerase II complexes, and DNA replication. Differential protein expression analysis established the networks linking histone hypoacetylation to the down-regulated expression/activity of p300 and linking histone H2B ubiquitination to the RNA polymerase II-associated FACT-RTF1-PAF1 complex. Collectively, our approach has provided an unprecedentedly systemic set of insights into the role of epigenetic regulation in leukemia cell differentiation.

[1]  L. Selth,et al.  Transcript Elongation by RNA Polymerase II. , 2010, Annual review of biochemistry.

[2]  Guoliang Xu,et al.  A Modified “Cross-talk” between Histone H2B Lys-120 Ubiquitination and H3 Lys-79 Methylation* , 2010, The Journal of Biological Chemistry.

[3]  G. Schmitz,et al.  Induction of fatty acid synthesis is a key requirement for phagocytic differentiation of human monocytes , 2010, Proceedings of the National Academy of Sciences.

[4]  Peng Wang,et al.  Development of mass spectrometry-based shotgun method for proteome analysis of 500 to 5000 cancer cells. , 2010, Analytical chemistry.

[5]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[6]  K. Stuhlmeier,et al.  Epigenetic regulation of dendritic cell differentiation and function by oxidized phospholipids. , 2009, Blood.

[7]  J. Acharya,et al.  Ceramide kinase regulates phospholipase C and phosphatidylinositol 4, 5, bisphosphate in phototransduction , 2009, Proceedings of the National Academy of Sciences.

[8]  Matthias Mann,et al.  A Dual Pressure Linear Ion Trap Orbitrap Instrument with Very High Sequencing Speed* , 2009, Molecular & Cellular Proteomics.

[9]  Guoliang Xu,et al.  Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells* , 2009, The Journal of Biological Chemistry.

[10]  Dominic T. Schomberg,et al.  Cellular Epigenetic Modifications of Neural Stem Cell Differentiation , 2009, Cell transplantation.

[11]  Xuetong Shen,et al.  Histone modifications during DNA replication , 2009, Molecules and cells.

[12]  Michael J MacCoss,et al.  Dual-pressure linear ion trap mass spectrometer improving the analysis of complex protein mixtures. , 2009, Analytical chemistry.

[13]  J. Plutzky.  Expansion and contraction: the mighty, mighty fatty acid , 2009, Nature Medicine.

[14]  L. Sowers,et al.  Enzymatic methylation of DNA in cultured human cells studied by stable isotope incorporation and mass spectrometry. , 2009, Chemical research in toxicology.

[15]  J. Olefsky.  Fat Talks, Liver and Muscle Listen , 2008, Cell.

[16]  S. Watkins,et al.  Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism , 2008, Cell.

[17]  T. Nakayama,et al.  Histone acetyltransferase-1 regulates integrity of cytosolic histone H3-H4 containing complex. , 2008, Biochemical and biophysical research communications.

[18]  H. Masai,et al.  Cdt1 Forms a Complex with the Minichromosome Maintenance Protein (MCM) and Activates Its Helicase Activity* , 2008, Journal of Biological Chemistry.

[19]  A. Knox,et al.  PKCβΙΙ Augments NF-κB-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation1 , 2008, The Journal of Immunology.

[20]  Michael Grunstein,et al.  Adenovirus Small e1a Alters Global Patterns of Histone Modification , 2008, Science.

[21]  J. Jaehning,et al.  Direct Interactions between the Paf1 Complex and a Cleavage and Polyadenylation Factor Are Revealed by Dissociation of Paf1 from RNA Polymerase II , 2008, Eukaryotic Cell.

[22]  Brian D. Strahl,et al.  Unlocking Cell Fate , 2007, Science.

[23]  S. Jacobsen,et al.  UHRF1 Plays a Role in Maintaining DNA Methylation in Mammalian Cells , 2007, Science.

[24]  A. Häkkinen,et al.  Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity , 2007, Diabetes.

[25]  Kelli L. Roinick,et al.  Rtf1 Is a Multifunctional Component of the Paf1 Complex That Regulates Gene Expression by Directing Cotranscriptional Histone Modification , 2007, Molecular and Cellular Biology.

[26]  M. Agarwal,et al.  DNA replication licensing factor minichromosome maintenance deficient 5 rescues p53-mediated growth arrest. , 2007, Cancer research.

[27]  N. Planque,et al.  Nuclear trafficking of secreted factors and cell-surface receptors: new pathways to regulate cell proliferation and differentiation, and involvement in cancers , 2006, Cell Communication and Signaling.

[28]  D. Reinberg,et al.  Histone H2B Monoubiquitination Functions Cooperatively with FACT to Regulate Elongation by RNA Polymerase II , 2006, Cell.

[29]  R. Coleman,et al.  Rat Long Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Uptake and Partitioning to Cellular Triacylglycerol in McArdle-RH7777 Cells* , 2006, Journal of Biological Chemistry.

[30]  Paul Tempst,et al.  Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. , 2005, Molecular cell.

[31]  L. Hinrichsen,et al.  Effect of Clathrin Assembly Lymphoid Myeloid Leukemia Protein Depletion on Clathrin Coat Formation , 2005, Traffic.

[32]  Min Jae Lee,et al.  A Family of Mammalian E3 Ubiquitin Ligases That Contain the UBR Box Motif and Recognize N-Degrons , 2005, Molecular and Cellular Biology.

[33]  E. Rothenberg,et al.  Cell-type-specific epigenetic marking of the IL2 gene at a distal cis-regulatory region in competent, nontranscribing T-cells , 2005, Nucleic acids research.

[34]  D. Takeda,et al.  DNA replication and progression through S phase , 2005, Oncogene.

[35]  E. Benveniste,et al.  Coordination of Cell Signaling, Chromatin Remodeling, Histone Modifications, and Regulator Recruitment in Human Matrix Metalloproteinase 9 Gene Transcription , 2004, Molecular and Cellular Biology.

[36]  Hua Lu,et al.  MDM2 Mediates p300/CREB-binding Protein-associated Factor Ubiquitination and Degradation* , 2004, Journal of Biological Chemistry.

[37]  F. Brouillard,et al.  Concomitant Increase of Histone Acetyltransferase Activity and Degradation of p300 during Retinoic Acid-induced Differentiation of F9 Cells* , 2003, Journal of Biological Chemistry.

[38]  Mark Johnston,et al.  The Paf1 Complex Is Essential for Histone Monoubiquitination by the Rad6-Bre1 Complex, Which Signals for Histone Methylation by COMPASS and Dot1p* , 2003, Journal of Biological Chemistry.

[39]  Kevin Struhl,et al.  The Rtf1 Component of the Paf1 Transcriptional Elongation Complex Is Required for Ubiquitination of Histone H2B* , 2003, Journal of Biological Chemistry.

[40]  K. Sullivan,et al.  Histone acetylation and chromatin conformation are regulated separately at the TNF‐α promoter in monocytes and macrophages , 2003, Journal of leukocyte biology.

[41]  G. Morgan,et al.  Epigenetic consequences of AML1–ETO action at the human c‐FMS locus , 2003, The EMBO journal.

[42]  C. Allis,et al.  Histone and chromatin cross-talk. , 2003, Current opinion in cell biology.

[43]  R. Poot,et al.  An ACF1–ISWI chromatin-remodeling complex is required for DNA replication through heterochromatin , 2002, Nature Genetics.

[44]  B. Cairns,et al.  Transcriptional inhibition of genes with severe histone h3 hypoacetylation in the coding region. , 2002, Molecular cell.

[45]  Bert Vogelstein,et al.  DNMT1 and DNMT3b cooperate to silence genes in human cancer cells , 2002, Nature.

[46]  Huitu Liu,et al.  MAPK signal pathways in the regulation of cell proliferation in mammalian cells , 2002, Cell Research.

[47]  A. Annunziato,et al.  Effects of Acetylation of Histone H4 at Lysines 8 and 16 on Activity of the Hat1 Histone Acetyltransferase* , 2001, The Journal of Biological Chemistry.

[48]  J. Hurwitz,et al.  Processive DNA helicase activity of the minichromosome maintenance proteins 4, 6, and 7 complex requires forked DNA structures. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[49]  L. Kedes,et al.  Proteasome-Mediated Degradation of the Coactivator p300 Impairs Cardiac Transcription , 2000, Molecular and Cellular Biology.

[50]  C. L. Jackson,et al.  Regulators and effectors of the ARF GTPases. , 2000, Current opinion in cell biology.

[51]  J. Jelinek,et al.  Chromatin remodeling gene SMARCA5 is dysregulated in primitive hematopoietic cells of acute leukemia , 2000, Leukemia.

[52]  A. Harel-Bellan,et al.  CBP/p300 histone acetyl-transferase activity is important for the G1/S transition , 2000, Oncogene.

[53]  B. Stillman,et al.  A double-hexamer archaeal minichromosome maintenance protein is an ATP-dependent DNA helicase. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[54]  S. Bohlander,et al.  Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. , 1999, Molecular biology of the cell.

[55]  K. Sandhoff,et al.  Sphingolipid Metabolism: Sphingoid Analogs, Sphingolipid Activator Proteins, and the Pathology of the Cell a , 1998 .

[56]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[57]  R. Weichselbaum,et al.  Protein kinase C inhibition induces apoptosis and ceramide production through activation of a neutral sphingomyelinase. , 1996, Cancer research.

[58]  Y. Hannun,et al.  Ceramide Inactivates Cellular Protein Kinase Cα* , 1996, The Journal of Biological Chemistry.

[59]  J. Rowley,et al.  The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[60]  James P. J. Chong,et al.  Purification of an MCM-containing complex as a component of the DNA replication licensing system , 1995, Nature.

[61]  Mark D. Johnson,et al.  Overproduction of protein kinase C causesdisordered growth control in rat fibroblasts , 1988, Cell.

[62]  T. Hattori,et al.  Interferon-induced differentiation of U937 cells. Comparison with other agents that promote differentiation of human myeloid or monocytelike cell lines. , 1983, The Journal of clinical investigation.