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• W2606941712 abstract "Three-dimensional organization of transcription in the nucleus and mechanisms controlling the global chromatin folding, including spatial interactions between the genes, noncoding genome elements, and epigenetic and transcription machinery, are essential for establishing lineage-specific gene expression programs during cell differentiation. Spatial chromatin interactions in the nucleus involving gene promoters and distal regulatory elements are currently considered major forces that drive cell differentiation and genome evolution in general, and such interactions are substantially reorganized during many pathological conditions. During terminal differentiation of the epidermal keratinocytes, the nucleus undergoes programmed transformation from highly active status, associated with execution of the genetic program of epidermal barrier formation, to a fully inactive condition and finally becomes a part of the keratinized cells of the cornified epidermal layer. This transition is accompanied by marked remodeling of the three-dimensional nuclear organization and microanatomy, including changes in the spatial arrangement of lineage-specific genes, nuclear bodies, and heterochromatin. This mini-review highlights the important landmarks in the accumulation of our current knowledge on three-dimensional organization of the nucleus, spatial arrangement of the genes, and their distal regulatory elements, and it provides an update on the mechanisms that control higher-order chromatin remodeling in the context of epidermal keratinocyte differentiation in the skin. Three-dimensional organization of transcription in the nucleus and mechanisms controlling the global chromatin folding, including spatial interactions between the genes, noncoding genome elements, and epigenetic and transcription machinery, are essential for establishing lineage-specific gene expression programs during cell differentiation. Spatial chromatin interactions in the nucleus involving gene promoters and distal regulatory elements are currently considered major forces that drive cell differentiation and genome evolution in general, and such interactions are substantially reorganized during many pathological conditions. During terminal differentiation of the epidermal keratinocytes, the nucleus undergoes programmed transformation from highly active status, associated with execution of the genetic program of epidermal barrier formation, to a fully inactive condition and finally becomes a part of the keratinized cells of the cornified epidermal layer. This transition is accompanied by marked remodeling of the three-dimensional nuclear organization and microanatomy, including changes in the spatial arrangement of lineage-specific genes, nuclear bodies, and heterochromatin. This mini-review highlights the important landmarks in the accumulation of our current knowledge on three-dimensional organization of the nucleus, spatial arrangement of the genes, and their distal regulatory elements, and it provides an update on the mechanisms that control higher-order chromatin remodeling in the context of epidermal keratinocyte differentiation in the skin. Three-dimensional (3D) organization of transcription in the nucleus and mechanisms controlling global chromatin folding, including spatial interactions between the genes, noncoding genome elements, and epigenetic and transcription machinery, are essential for establishing lineage-specific gene expression programs during cell differentiation (Bickmore, 2013Bickmore W.A. The spatial organization of the human genome.Annu Rev Genomics Hum Genet. 2013; 14: 67-84Crossref PubMed Scopus (254) Google Scholar, Chakalova and Fraser, 2010Chakalova L. Fraser P. Organization of transcription.Cold Spring Harb Perspect Biol. 2010; 2: a000729Crossref PubMed Scopus (58) Google Scholar, Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar, Gomez-Diaz and Corces, 2014Gomez-Diaz E. Corces V.G. Architectural proteins: regulators of 3D genome organization in cell fate.Trends Cell Biol. 2014; 24: 703-711Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, Sequeira-Mendes and Gutierrez, 2015Sequeira-Mendes J. Gutierrez C. Genome architecture: from linear organisation of chromatin to the 3D assembly in the nucleus.Chromosoma. 2015; 125: 455-469Crossref PubMed Scopus (22) Google Scholar). During the last decade, tremendous progress has been achieved in understanding the functional microanatomy of the nucleus as a dynamic structure, in which actively transcribed or repressed genes are spatially compartmentalized into distinct domains and frequently form preferential intra- and interchromosomal interactomes, which provide functional and structural frameworks for cell-specific transcription (Dekker et al., 2013Dekker J. Marti-Renom M.A. Mirny L.A. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data.Nat Rev Genet. 2013; 14: 390-403Crossref PubMed Scopus (738) Google Scholar, Schoenfelder et al., 2010Schoenfelder S. Clay I. Fraser P. The transcriptional interactome: gene expression in 3D.Curr Opin Genet Dev. 2010; 20: 127-133Crossref PubMed Scopus (121) Google Scholar, Sexton and Cavalli, 2015Sexton T. Cavalli G. The role of chromosome domains in shaping the functional genome.Cell. 2015; 160: 1049-1059Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). The nucleus is a complex organelle that includes the nuclear membrane, chromosomes, and nucleoli and other nuclear bodies (nuclear speckles, promyelocytic leukemia bodies, Cajal bodies, etc.) that facilitate the execution of gene expression programs and other nuclear functions (Hubner and Spector, 2010Hubner M.R. Spector D.L. Chromatin dynamics.Annu Rev Biophys. 2010; 39: 471-489Crossref PubMed Scopus (119) Google Scholar, Lanctot et al., 2007Lanctot C. Cheutin T. Cremer M. Cavalli G. Cremer T. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions.Nat Rev Genet. 2007; 8: 104-115Crossref PubMed Scopus (629) Google Scholar, Mao et al., 2011Mao Y.S. Zhang B. Spector D.L. Biogenesis and function of nuclear bodies.Trends Genet. 2011; 27: 295-306Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar, Misteli, 2007Misteli T. Beyond the sequence: cellular organization of genome function.Cell. 2007; 128: 787-800Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar, Pederson, 2011Pederson T. The nucleus introduced.Cold Spring Harb Perspect Biol. 2011; 3: a000521Crossref Scopus (31) Google Scholar). Serving as a central hub in establishing adaptive cell behavior, the nucleus integrates the signals coming from the extracellular space and transforms them into specific gene expression programs to help cells survive and generate an appropriate response to changes in the microenvironment. During terminal differentiation of the epidermal keratinocytes, the nucleus undergoes programmed transformation from highly active status, associated with execution of the genetic program of epidermal barrier formation, to a fully inactive condition and finally becomes a part of the keratinized cells of the cornified epidermal layer. This transition is accompanied by marked remodeling of the 3D nuclear organization and microanatomy, including changes in the spatial arrangement of lineage-specific genes, nuclear bodies, and heterochromatin (Gdula et al., 2013Gdula M.R. Poterlowicz K. Mardaryev A.N. Sharov A.A. Peng Y. Fessing M.Y. et al.Remodeling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis.J Invest Dermatol. 2013; 133: 2191-2201Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). This mini-review highlights the important landmarks in the accumulation of our current knowledge of 3D organization of the nucleus and provides an update on the mechanisms that control higher-order chromatin remodeling in the context of epidermal keratinocyte differentiation in the skin. Chromosomes are the largest units of the genome organization, occupying distinct territories in the interphase nucleus (Cremer et al., 2001Cremer M. von Hase J. Volm T. Brero A. Kreth G. Walter J. et al.Non-random radial higher-order chromatin arrangements in nuclei of diploid human cells.Chromosome Res. 2001; 9: 541-567Crossref PubMed Scopus (318) Google Scholar, Cremer and Cremer, 2011Cremer T. Cremer M. Chromosome territories.in: Misteli T. Spector D.L. The nucleus. Cold Spring Harbor Laboratory Press, Cold-Spring Harbor, NY2011: 93-114Google Scholar, Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar) (Figure 1a). In the chromosomes, DNA is compacted up to several thousand-fold and organized into DNA-protein complex (chromatin) that allows the genome to be transcribed, replicated, and repaired (Hemberger et al., 2009Hemberger M. Dean W. Reik W. Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington's canal.Nat Rev Mol Cell Biol. 2009; 10: 526-537Crossref PubMed Scopus (384) Google Scholar, Ho and Crabtree, 2010Ho L. Crabtree G.R. Chromatin remodelling during development.Nature. 2010; 463: 474-484Crossref PubMed Scopus (803) Google Scholar, Sequeira-Mendes and Gutierrez, 2015Sequeira-Mendes J. Gutierrez C. Genome architecture: from linear organisation of chromatin to the 3D assembly in the nucleus.Chromosoma. 2015; 125: 455-469Crossref PubMed Scopus (22) Google Scholar). Each chromosome consists of the chromosome arms containing the gene-rich and gene-poor domains enriched in the guanine-cytosine and adenine-thymine sequences and visualized as the light and dark bands by Giemsa staining, respectively, as well as of a centromere (pericentromeric chromatin enriched in α-satellite repetitive sequences) and the telomeres (Fukui, 2009Fukui K. Structural analyses of chromosomes and their constituent proteins.Cytogenet Genome Res. 2009; 124: 215-227Crossref PubMed Scopus (12) Google Scholar). Chromosomes are visualized by 3D fluorescence in situ hybridization technique with specific paints that allow definition of their positions in the nucleus (Cremer and Cremer, 2010Cremer T. Cremer M. Chromosome territories.Cold Spring Harb Perspect Biol. 2010; 2: a003889Crossref PubMed Scopus (766) Google Scholar, Solovei and Cremer, 2010Solovei I. Cremer M. 3D-FISH on cultured cells combined with immunostaining.Methods Mol Biol. 2010; 659: 117-126Crossref PubMed Scopus (52) Google Scholar). The term chromosomal territory was first introduced by Theodor Boveri in 1909 (reviewed in Cremer and Cremer, 2006aCremer T. Cremer C. Rise, fall and resurrection of chromosome territories: a historical perspective. Part I. The rise of chromosome territories.Eur J Histochem. 2006; 50: 161-176PubMed Google Scholar, Cremer and Cremer, 2006bCremer T. Cremer C. Rise, fall and resurrection of chromosome territories: a historical perspective. Part II. Fall and resurrection of chromosome territories during the 1950s to 1980s. Part III. Chromosome territories and the functional nuclear architecture: experiments and models from the 1990s to the present.Eur J Histochem. 2006; 50: 223-272PubMed Google Scholar). Research in Thomas Cremer’s laboratory performed during the last three decades has brought tremendous progress in our understanding of the spatial organization of the genes and chromosomes in the interphase nucleus (for reviews, see Cremer and Cremer, 2001Cremer T. Cremer C. Chromosome territories, nuclear architecture and gene regulation in mammalian cells.Nat Rev Genet. 2001; 2: 292-301Crossref PubMed Scopus (1695) Google Scholar, Cremer and Cremer, 2011Cremer T. Cremer M. Chromosome territories.in: Misteli T. Spector D.L. The nucleus. Cold Spring Harbor Laboratory Press, Cold-Spring Harbor, NY2011: 93-114Google Scholar, Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar). Confocal microscopy analyses of tissue sections or isolated cells by using the whole chromosome 3D fluorescence in situ hybridization probes showed that in the interphase nucleus, the relative positioning of the chromosomes within the 3D nuclear space is not random and depends on many factors including the cell type, differentiation stage, chromosome size, and the gene-rich or gene-poor status (Cremer and Cremer, 2010Cremer T. Cremer M. Chromosome territories.Cold Spring Harb Perspect Biol. 2010; 2: a003889Crossref PubMed Scopus (766) Google Scholar). Data obtained from mouse skin in situ show that in basal epidermal keratinocytes, chromosome 3 harboring the epidermal differentiation complex (EDC) locus is always located at the nuclear periphery (Figure 1a and c), and its positioning does not change during embryonic and postnatal development or during terminal differentiation and keratinocyte transition to the spinous and granular epidermal layers (Fessing et al., 2011Fessing M.Y. Mardaryev A.N. Gdula M.R. Sharov A.A. Sharova T.Y. Rapisarda V. et al.p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis.J Cell Biol. 2011; 194: 825-839Crossref PubMed Scopus (129) Google Scholar, Gdula et al., 2013Gdula M.R. Poterlowicz K. Mardaryev A.N. Sharov A.A. Peng Y. Fessing M.Y. et al.Remodeling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis.J Invest Dermatol. 2013; 133: 2191-2201Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, Mardaryev et al., 2014Mardaryev A.N. Gdula M.R. Yarker J.L. Emelianov V.N. Poterlowicz K. Sharov A.A. et al.p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells.Development. 2014; 141: 101-111Crossref PubMed Scopus (62) Google Scholar). However, chromosomes 11 and 15, harboring keratin type I and type II loci, respectively, occupy predominantly central positions in the keratinocyte nuclei (Botchkarev et al., 2012Botchkarev V.A. Gdula M.R. Mardaryev A.N. Sharov A.A. Fessing M.Y. Epigenetic regulation of gene expression in keratinocytes.J Invest Dermatol. 2012; 132: 2505-2521Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). In the interphase nucleus, positioning of the chromosomes is controlled through several mechanisms, which include the interactions between specialized lamina-associated domains and nuclear lamina, as well as through association of the chromosomes bearing the nucleolar-organizing region domains with nucleoli (reviewed in Joffe et al., 2010Joffe B. Leonhardt H. Solovei I. Differentiation and large scale spatial organization of the genome.Curr Opin Genet Dev. 2010; 20: 562-569Crossref PubMed Scopus (52) Google Scholar, Kind and van Steensel, 2014Kind J. van Steensel B. Stochastic genome-nuclear lamina interactions: modulating roles of Lamin A and BAF.Nucleus. 2014; 5: 124-130Crossref PubMed Scopus (63) Google Scholar, McKeown and Shaw, 2009McKeown P.C. Shaw P.J. Chromatin: linking structure and function in the nucleolus.Chromosoma. 2009; 118: 11-23Crossref PubMed Scopus (73) Google Scholar, Misteli, 2007Misteli T. Beyond the sequence: cellular organization of genome function.Cell. 2007; 128: 787-800Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar). Distinct chromosomes may be arranged in the nuclei of differentiated cells in a cell lineage-specific manner, which explains an increased frequency of translocations between the distinct chromosomal parts in the corresponding tumors (Brianna Caddle et al., 2007Brianna Caddle L. Grant J.L. Szatkiewicz J. van Hase J. Shirley B.J. Bewersdorf J. et al.Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells.Chromosome Res. 2007; 15: 1061-1073Crossref PubMed Scopus (38) Google Scholar, Khalil et al., 2007Khalil A. Grant J.L. Caddle L.B. Atzema E. Mills K.D. Arneodo A. Chromosome territories have a highly nonspherical morphology and nonrandom positioning.Chromosome Res. 2007; 15: 899-916Crossref PubMed Scopus (75) Google Scholar, Parada et al., 2004Parada L.A. Sotiriou S. Misteli T. Spatial genome organization.Exp Cell Res. 2004; 296: 64-70Crossref PubMed Scopus (75) Google Scholar, Roix et al., 2003Roix J.J. McQueen P.G. Munson P.J. Parada L.A. Misteli T. Spatial proximity of translocation-prone gene loci in human lymphomas.Nat Genet. 2003; 34: 287-291Crossref PubMed Scopus (349) Google Scholar). However, it is unclear whether genes from neighboring chromosomes may share common regulatory mechanisms required for their transcription (Cremer and Cremer, 2011Cremer T. Cremer M. Chromosome territories.in: Misteli T. Spector D.L. The nucleus. Cold Spring Harbor Laboratory Press, Cold-Spring Harbor, NY2011: 93-114Google Scholar). Introduction of superresolution confocal microscopy allowed improvement in the resolution of fluorescence images up to 20–100 nm and served as an important next step in the analysis of nuclear architecture (Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar, Schermelleh et al., 2010Schermelleh L. Heintzmann R. Leonhardt H. A guide to super-resolution fluorescence microscopy.J Cell Biol. 2010; 190: 165-175Crossref PubMed Scopus (977) Google Scholar). Superresolution confocal microscopy showed that chromosome territories consist of the chromatin domains permeated by a network of interchromatin channels connected with the larger channels separating distinct chromosomes (Markaki et al., 2010Markaki Y. Gunkel M. Schermelleh L. Beichmanis S. Neumann J. Heidemann M. et al.Functional nuclear organization of transcription and DNA replication: a topographical marriage between chromatin domains and the interchromatin compartment.Cold Spring Harb Symp Quant Biol. 2010; 75: 475-492Crossref PubMed Scopus (109) Google Scholar). Interchromatin channels also serve as a reservoir for macromolecular complexes, transcription factors, regulators of splicing, replication, and repair, as well as for exporting the mRNA-containing ribonucleoprotein complexes (Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar). The chromatin domains in each territory are separated from the interchromatin channels by a layer of decondensed chromatin (perichromatin), which is enriched by RNA polymerase II and the histone modification H3K4me3 specific for transcriptionally active chromatin (Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar, Markaki et al., 2010Markaki Y. Gunkel M. Schermelleh L. Beichmanis S. Neumann J. Heidemann M. et al.Functional nuclear organization of transcription and DNA replication: a topographical marriage between chromatin domains and the interchromatin compartment.Cold Spring Harb Symp Quant Biol. 2010; 75: 475-492Crossref PubMed Scopus (109) Google Scholar). These observations were further developed into a model that suggests the presence of the active and inactive nuclear compartments inside each chromosome territory that harbor transcriptionally active or inactive genes, respectively (Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar) (Figure 1b). This model also suggests a large degree of flexibility in the positioning of distinct chromatin domains inside each chromosome territory, which corresponds well to the fact that some gene loci (IFN-γ and T helper type 2 cytokine loci in TH lymphocytes, globin genes in erythroid cells, Nanog locus in induced pluripotent stem cells) may change their positioning relative to other loci or to the corresponding chromosomal territories associated with either gene activation or silencing (Spilianakis et al., 2005Spilianakis C.G. Lalioti M.D. Town T. Lee G.R. Flavell R.A. Interchromosomal associations between alternatively expressed loci.Nature. 2005; 435: 637-645Crossref PubMed Scopus (567) Google Scholar, Schoenfelder et al., 2010Schoenfelder S. Clay I. Fraser P. The transcriptional interactome: gene expression in 3D.Curr Opin Genet Dev. 2010; 20: 127-133Crossref PubMed Scopus (121) Google Scholar, Jost et al., 2011Jost K.L. Haase S. Smeets D. Schrode N. Schmiedel J.M. Bertulat B. et al.3D-image analysis platform monitoring relocation of pluripotency genes during reprogramming.Nucleic Acids Res. 2011; 39: e113Crossref PubMed Scopus (17) Google Scholar). During epidermal morphogenesis and differentiation of the basal epidermal progenitor cells, the genomic domain on mouse chromosome 3 harboring the EDC locus shows a remarkable plasticity in the higher-order chromatin structure relocating from the nuclear periphery toward the internal part of chromosomal territory 3 and the nuclear interior (Mardaryev et al., 2014Mardaryev A.N. Gdula M.R. Yarker J.L. Emelianov V.N. Poterlowicz K. Sharov A.A. et al.p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells.Development. 2014; 141: 101-111Crossref PubMed Scopus (62) Google Scholar) (Figure 1c). Such developmentally regulated relocation occurs only in the epidermal keratinocytes, but not in dermal cells, and is associated with a marked increase in the transcription of the terminal differentiation-associated genes involved in the control of epidermal barrier formation (Mardaryev et al., 2014Mardaryev A.N. Gdula M.R. Yarker J.L. Emelianov V.N. Poterlowicz K. Sharov A.A. et al.p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells.Development. 2014; 141: 101-111Crossref PubMed Scopus (62) Google Scholar). The keratinocyte-specific EDC positioning in the nuclear interior is maintained through many cycles of cell division until adulthood (Mardaryev et al., 2014Mardaryev A.N. Gdula M.R. Yarker J.L. Emelianov V.N. Poterlowicz K. Sharov A.A. et al.p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells.Development. 2014; 141: 101-111Crossref PubMed Scopus (62) Google Scholar). These data are consistent with a previous report showing that EDC locus positioning relative to chromosome territory 1 in cultured human keratinocytes is changed during differentiation (Williams et al., 2002Williams R.R. Broad S. Sheer D. Ragoussis J. Subchromosomal positioning of the epidermal differentiation complex (EDC) in keratinocyte and lymphoblast interphase nuclei.Exp Cell Res. 2002; 272: 163-175Crossref PubMed Scopus (167) Google Scholar). Developmentally regulated repositioning of the EDC locus into the nuclear interior is associated with an increase in its close vicinity in the number of SC-35 nuclear speckles (Mardaryev et al., 2014Mardaryev A.N. Gdula M.R. Yarker J.L. Emelianov V.N. Poterlowicz K. Sharov A.A. et al.p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells.Development. 2014; 141: 101-111Crossref PubMed Scopus (62) Google Scholar), which are considered to be the sites of the association between active genes within the nucleus (Brown et al., 2008Brown J.M. Green J. das Neves R.P. Wallace H.A. Smith A.J. Hughes J. et al.Association between active genes occurs at nuclear speckles and is modulated by chromatin environment.J Cell Biol. 2008; 182: 1083-1097Crossref PubMed Scopus (193) Google Scholar, Mao et al., 2011Mao Y.S. Zhang B. Spector D.L. Biogenesis and function of nuclear bodies.Trends Genet. 2011; 27: 295-306Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar, Popken et al., 2014Popken J. Brero A. Koehler D. Schmid V.J. Strauss A. Wuensch A. et al.Reprogramming of fibroblast nuclei in cloned bovine embryos involves major structural remodeling with both striking similarities and differences to nuclear phenotypes of in vitro fertilized embryos.Nucleus. 2014; 5: 555-589Crossref PubMed Scopus (33) Google Scholar, Spector and Lamond, 2011Spector D.L. Lamond A.I. Nuclear speckles.Cold Spring Harb Perspect Biol. 2011; 3: a000646Crossref Scopus (521) Google Scholar, Szczerbal and Bridger, 2010Szczerbal I. Bridger J.M. Association of adipogenic genes with SC-35 domains during porcine adipogenesis.Chromosome Res. 2010; 18: 887-895Crossref PubMed Scopus (35) Google Scholar). Nuclear speckles are nuclear bodies containing important constituents of the pre-mRNA processing machinery, such as polyadenylation and splicing factors including small nuclear ribonuclear proteins, poly-A+ RNA, and other splicing-related proteins (Spector and Lamond, 2011Spector D.L. Lamond A.I. Nuclear speckles.Cold Spring Harb Perspect Biol. 2011; 3: a000646Crossref Scopus (521) Google Scholar). Many of these factors are either recruited to transcription sites from the speckles or are involved in mRNA processing in the speckles (Spector and Lamond, 2011Spector D.L. Lamond A.I. Nuclear speckles.Cold Spring Harb Perspect Biol. 2011; 3: a000646Crossref Scopus (521) Google Scholar). Nuclear speckles are also considered as the sites of accumulation of the noncoding RNAs including MALAT1, which interacts with RNA-binding proteins and targets pre-mRNAs at sites of active transcription (Engreitz et al., 2014Engreitz J.M. Sirokman K. McDonel P. Shishkin A.A. Surka C. Russell P. et al.RNA-RNA interactions enable specific targeting of noncoding RNAs to nascent Pre-mRNAs and chromatin sites.Cell. 2014; 159: 188-199Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar). Nuclear speckles may provide a “permissive environment” for the efficient transcription of the genes activated during terminal keratinocyte differentiation. However, the impact of the distinct speckle components in the control of gene expression within the EDC and other keratinocyte-specific gene loci remains to be further determined. Terminal differentiation of the epidermal keratinocytes is also accompanied by marked changes in the microanatomical organization of the nucleus, including a decrease of the nuclear volume, a decrease in expression of the markers of transcriptionally active chromatin, a decrease in the number of nucleoli, and an increase in the number of pericentromeric heterochromatic clusters and the frequency of associations between nucleoli, pericentromeric clusters, and chromosomal territory 3 (Gdula et al., 2013Gdula M.R. Poterlowicz K. Mardaryev A.N. Sharov A.A. Peng Y. Fessing M.Y. et al.Remodeling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis.J Invest Dermatol. 2013; 133: 2191-2201Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar) (Figure 1d). The changes in the nuclear microanatomy are likely to be associated with global changes in the transcriptional landscape in terminally differentiating keratinocytes that occurred during transition of the keratinocyte nucleus from metabolically active to inactive status (Gdula et al., 2013Gdula M.R. Poterlowicz K. Mardaryev A.N. Sharov A.A. Peng Y. Fessing M.Y. et al.Remodeling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis.J Invest Dermatol. 2013; 133: 2191-2201Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). These data also suggest the nucleoli and pericentromeric clusters as important elements of the nuclear architecture that may control the local “transcriptional microenvironment” of the distinct chromatin domains by modulating the processes of chromosome tethering and regulating their positioning, folding, and/or orientation. Spatial proximity of the genes and chromosomes in the nucleus plays an important role in the occurrence of chromosomal translocations during neoplastic transformation: neighboring chromosomes show higher frequencies of translocations compared with distal chromosomes, and translocations are formed predominantly between proximal chromosome breaks (Roukos and Misteli, 2014Roukos V. Misteli T. The biogenesis of chromosome translocations.Nat Cell Biol. 2014; 16: 293-300Crossref PubMed Scopus (110) Google Scholar). 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• W2606941712 created "2017-04-28" @default.
• W2606941712 creator A5090650222 @default.
• W2606941712 date "2017-05-01" @default.
• W2606941712 modified "2023-10-18" @default.
• W2606941712 title "The Molecular Revolution in Cutaneous Biology: Chromosomal Territories, Higher-Order Chromatin Remodeling, and the Control of Gene Expression in Keratinocytes" @default.
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