Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions

The promyelocytic leukemia (PML) protein is aggregated into nuclear bodies that are associated with diverse nuclear processes. Here, we report that the distance between a locus and its nearest PML body correlates with the transcriptional activity and gene density around the locus. Genes on the active X chromosome are more significantly associated with PML bodies than their silenced homologues on the inactive X chromosome. We also found that a histone-encoding gene cluster, which is transcribed only in S-phase, is more strongly associated with PML bodies in S-phase than in G0/G1 phase of the cell cycle. However, visualization of specific RNA transcripts for several genes showed that PML bodies were not themselves sites of transcription for these genes. Furthermore, knock-down of PML bodies by RNA interference did not preferentially change the expression of genes closely associated with PML bodies. We propose that PML bodies form in nuclear compartments of high transcriptional activity, but they do not directly regulate transcription of genes in these compartments.

[1]  P. Freemont,et al.  PML protein isoforms and the RBCC/TRIM motif , 2001, Oncogene.

[2]  Christine Chomienne,et al.  The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR , 1991, Cell.

[3]  Carolyn J. Brown,et al.  A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome , 1991, Nature.

[4]  A. Matera,et al.  Coiled bodies contain U7 small nuclear RNA and associate with specific DNA sequences in interphase human cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. von Mikecz,et al.  Cell cycle-dependent association of PML bodies with sites of active transcription in nuclei of mammalian cells. , 2002, Journal of structural biology.

[6]  R. Morimoto,et al.  In vivo binding of active heat shock transcription factor 1 to human chromosome 9 heterochromatin during stress , 2002, The Journal of cell biology.

[7]  D. Levy,et al.  Proto-oncogene PML controls genes devoted to MHC class I antigen presentation , 1998, Nature.

[8]  Wendy A. Bickmore,et al.  Spatial organization of active and inactive genes and noncoding DNA within chromosome territories , 2002, The Journal of cell biology.

[9]  M J Sternberg,et al.  PML bodies associate specifically with the MHC gene cluster in interphase nuclei. , 2001, Journal of cell science.

[10]  P. Hozák,et al.  Nuclear DNA helicase II is recruited to IFN-α–activated transcription sites at PML nuclear bodies , 2002, The Journal of cell biology.

[11]  A. Dejean,et al.  The PML nuclear bodies: actors or extras? , 1999, Current opinion in genetics & development.

[12]  F. Baas,et al.  The Human Transcriptome Map: Clustering of Highly Expressed Genes in Chromosomal Domains , 2001, Science.

[13]  Maria Carmo-Fonseca,et al.  Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells , 1994, Cell.

[14]  P. Thomas,et al.  Interferon gamma regulates accumulation of the proteasome activator PA28 and immunoproteasomes at nuclear PML bodies. , 2001, Journal of cell science.

[15]  P. Freemont,et al.  Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. , 1991, Science.

[16]  Ki-Hwan Lee,et al.  Differential gene expression in retinoic acid-induced differentiation of acute promyelocytic leukemia cells, NB4 and HL-60 cells. , 2002, Biochemical and biophysical research communications.

[17]  J. Ragoussis,et al.  Subchromosomal positioning of the epidermal differentiation complex (EDC) in keratinocyte and lymphoblast interphase nuclei. , 2002, Experimental cell research.

[18]  Zhi-xiang Xu,et al.  The Promyelocytic Leukemia Protein Represses A20-mediated Transcription* , 2002, The Journal of Biological Chemistry.

[19]  Wendy A Bickmore,et al.  Chromatin Motion Is Constrained by Association with Nuclear Compartments in Human Cells , 2002, Current Biology.

[20]  J. Ragoussis,et al.  Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei. , 2000, Journal of cell science.

[21]  N. Ellis,et al.  Regulation and Localization of the Bloom Syndrome Protein in Response to DNA Damage , 2001, The Journal of cell biology.

[22]  R. Evans,et al.  Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Regad,et al.  Role and fate of PML nuclear bodies in response to interferon and viral infections , 2001, Oncogene.

[24]  P. Pandolfi,et al.  The puzzling multiple lives of PML and its role in the genesis of cancer. , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[25]  J. Sobczak-Thépot,et al.  The PML growth-suppressor has an altered expression in human oncogenesis. , 1995, Oncogene.

[26]  M. Montminy,et al.  Creb-Binding Protein (Cbp/P300) and RNA Polymerase II Colocalize in Transcriptionally Active Domains in the Nucleus , 2000, The Journal of cell biology.

[27]  E. Besa.  Acute promyelocytic leukemia. , 1991, Blood.

[28]  P. Lichter,et al.  Identification of an interchromosomal compartment by polymerization of nuclear-targeted vimentin. , 1998, Journal of cell science.

[29]  P. van Endert.  Genes regulating MHC class I processing of antigen. , 1999, Current opinion in immunology.

[30]  P. Pelicci,et al.  The PML gene is not involved in the regulation of MHC class I expression in human cell lines. , 2003, Blood.

[31]  M. Bustin,et al.  The HMG-14/-17 chromosomal protein family: architectural elements that enhance transcription from chromatin templates. , 1995, Seminars in cell biology.

[32]  David S. Lapointe,et al.  Gene profiling of cell cycle progression through S-phase reveals sequential expression of genes required for DNA replication and nucleosome assembly. , 2002, Cancer research.

[33]  J. Lawrence,et al.  Replication-dependent histone gene expression is related to Cajal body (CB) association but does not require sustained CB contact. , 2001, Molecular biology of the cell.

[34]  Mamoru Ito,et al.  A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF , 2001, Leukemia.

[35]  G. Maul,et al.  Cellular proteins localized at and interacting within ND10/PML nuclear bodies/PODs suggest functions of a nuclear depot , 2001, Oncogene.

[36]  R. Evans,et al.  A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein , 1994, Cell.

[37]  R. Tjian,et al.  Targeting genes and transcription factors to segregated nuclear compartments. , 2003, Current opinion in cell biology.

[38]  U. Boehm,et al.  Cellular responses to interferon-gamma. , 1997, Annual review of immunology.

[39]  A. Fisher,et al.  Expression of α- and β-globin genes occurs within different nuclear domains in haemopoietic cells , 2001, Nature Cell Biology.

[40]  Peter Teague,et al.  Differences in the Localization and Morphology of Chromosomes in the Human Nucleus , 1999, The Journal of cell biology.

[41]  H. Willard,et al.  A first-generation X-inactivation profile of the human X chromosome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Ailan Guo,et al.  The function of PML in p53-dependent apoptosis , 2000, Nature Cell Biology.

[43]  S. Minucci,et al.  PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage , 2002, Oncogene.

[44]  J. Mattson.  Acute promyelocytic leukemia. From morphology to molecular lesions. , 2000, Clinics in Laboratory Medicine.

[45]  J. Chiche,et al.  Structural and Functional Heterogeneity of Nuclear Bodies , 1999, Molecular and Cellular Biology.

[46]  K. Umesono,et al.  Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML , 1991, Cell.

[47]  R Eils,et al.  Three-dimensional reconstruction of painted human interphase chromosomes: active and inactive X chromosome territories have similar volumes but differ in shape and surface structure , 1996, The Journal of cell biology.

[48]  K. Chang,et al.  The Promyelocytic Leukemia Protein Interacts with Sp1 and Inhibits Its Transactivation of the Epidermal Growth Factor Receptor Promoter , 1998, Molecular and Cellular Biology.

[49]  P. Pandolfi,et al.  Regulation of Pax3 transcriptional activity by SUMO-1-modified PML , 2001, Oncogene.

[50]  F. Boisvert,et al.  The Transcription Coactivator Cbp Is a Dynamic Component of the Promyelocytic Leukemia Nuclear Body , 2001, The Journal of cell biology.

[51]  J. R. Coleman,et al.  Processing of Endogenous Pre-mRNAs in Association with SC-35 Domains Is Gene Specific , 1999, The Journal of cell biology.

[52]  F. Denizot,et al.  Cloning of two novel ABC transporters mapping on human chromosome 9. , 1994, Genomics.

[53]  K. Borden,et al.  Pondering the Promyelocytic Leukemia Protein (PML) Puzzle: Possible Functions for PML Nuclear Bodies , 2002, Molecular and Cellular Biology.

[54]  R Eils,et al.  The 3D positioning of ANT2 and ANT3 genes within female X chromosome territories correlates with gene activity. , 1999, Experimental cell research.

[55]  François-Michel Boisvert,et al.  Promyelocytic Leukemia (Pml) Nuclear Bodies Are Protein Structures That Do Not Accumulate RNA , 2000, The Journal of cell biology.

[56]  D. Spector,et al.  Visualization of gene activity in living cells , 2000, Nature Cell Biology.

[57]  T. Cremer,et al.  Chromosome territories, nuclear architecture and gene regulation in mammalian cells , 2001, Nature Reviews Genetics.

[58]  R. Warrell,et al.  Acute promyelocytic leukemia. , 1993, The New England journal of medicine.

[59]  Tom Misteli,et al.  Spatial proximity of translocation-prone gene loci in human lymphomas , 2003, Nature Genetics.

[60]  Kenji Matsuno,et al.  Notch signaling. , 1995, Science.