title: Mass spectrometric studies on epigenetic interaction networks in cell differentiation.
abstract: 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.
authors.affiliation: Department of Chemistry, University of California, Riverside, California 92521, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.forename: Agus
authors.initials: A
authors.lastname: Darwanto
authors.forename: Seema
authors.initials: S
authors.lastname: Sharma
authors.forename: Jason
authors.initials: J
authors.lastname: Herring
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.forename: Maria
authors.initials: M
authors.lastname: Filippova
authors.forename: Valery
authors.initials: V
authors.lastname: Filippov
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Duerksen-Hughes
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Sowers
authors.forename: Kangling
authors.initials: K
authors.lastname: Zhang
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D020298:U937 Cells