A direct demonstration of somatically paired heterochromatin of human chromosomes

Schmid, Michael; Grunert, D.; Haaf, Thomas; Engel, Wolfgang

doi:10.1159/000131972

Cited by 102 publications

(45 citation statements)

References 5 publications

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“…We suggest that methylation abnormalities are intrinsically and directly involved in the generation of the second type of instability, thus allowing for the selection of MET Ϫ cells during the clonal evolution of tumors. This hypothesis is supported by the observation that demethylation is associated with chromosomal aberrations, including mitotic dysfunction and translocation (48,49), and is consistent with the innovative hypothesis relating methylation and aneuploidy recently put forward by Thomas (50).…”

Section: Discussionsupporting

confidence: 83%

DNA methylation and genetic instability in colorectal cancer cells

Lengauer

Kinzler

Vogelstein

1997

Proc. Natl. Acad. Sci. U.S.A.

357

221

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Apparent alterations in DNA methylation have been observed in many cancers, but whether such alterations represent a persistent alteration in the normal methylation process is not known. In this study, we report a striking difference in the expression of exogenously introduced retroviral genes in various colorectal cancer cell lines. Extinguished expression was associated with DNA methylation and could be reversed by treatment with the demethylating agent 5-azacytidine. A striking correlation between genetic instability and methylation capacity suggested that methylation abnormalities may play a role in chromosome segregation processes in cancer cells.

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Section: Discussionsupporting

confidence: 83%

DNA methylation and genetic instability in colorectal cancer cells

Lengauer

Kinzler

Vogelstein

1997

Proc. Natl. Acad. Sci. U.S.A.

357

221

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“…To induce undercondensation of constitutive heterochromatin, the base analog 5-aza-C was added to growing cultures 7 h before cell harvesting to give a final concentration of 0.3 mM in the medium (Schmid et al, 1983;1984a). The highest incidence of metaphases with undercondensation of latereplicating X l chromosomes was achieved when 5-aza-dC was added at a final concentration of 10 mM 2 h before harvesting (Haaf et al, 1988;.…”

Section: Methodsmentioning

confidence: 99%

Experimental condensation inhibition in constitutive and facultative heterochromatin of mammalian chromosomes

Haaf

Schmid

2000

Cytogenet Genome Res

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What drives the dramatic changes in chromosome structure during the cell cycle is one of the oldest questions in genetics. During mitosis, all chromosomes become highly condensed and, as the cell completes mitosis, most of the chromatin decondenses again. Only chromosome regions containing constitutive or facultative heterochromatin remain in a more condensed state throughout interphase. One approach to understanding chromosome condensation is to experimentally induce condensation defects. 5-Azacytidine (5-aza-C) and 5-azadeoxycytidine (5-aza-dC) drastically inhibit condensation in mammalian constitutive heterochromatin, in particular in human chromosomes 1, 9, 15, 16, and Y, as well as in facultative heterochromatin (inactive X chromosome), when incorporated into late-replicating DNA during the last hours of cell culture. The decondensing effects of 5-aza-C analogs, which do not interfere with normal base pairing in substituted duplex DNA, have been correlated with global DNA hypomethylation. In contrast, decondensation of constitutive heterochromatin by incorporation of 5-iododeoxyuridine (IdU) or other non-demethylating base analogs, or binding of AT-specific DNA ligands, such as berenil and Hoechst 33258, may reflect an altered steric configuration of substituted or minor-groove-bound duplex DNA. Consequently, these compounds exert relatively specific effects on certain subsets of AT-rich constitutive heterochromatin, i.e. IdU on human chromosome 9, berenil on human Y, and Hoechst 33258 on mouse chromosomes, which provide high local concentrations of IdU incorporation sites or DNA-ligand-binding sites. None of these non-demethylating compounds affect the inactive X chromosome condensation. Structural features of chromosomes are largely determined by chromosome-associated proteins. In this light, we propose that both DNA hypomethylation and steric alterations in chromosomal DNA may interfere with the binding of specific proteins or multi-protein complexes that are required for chromosome condensation. The association between chromosome condensation defects, genomic instability, and epigenetic reprogramming is discussed. Chromosome condensation may represent a key ancestral mechanism for modulating chromatin structure that has since been realloted to other nuclear processes.

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“…The juxtacentromeric satellite DNA, which is late replicating, participates in the somatic pairing of heterochromatic regions during the G2 phase (Schmid et al, 1983). Such properties imply that the satellite DNA needs to be disentangled and recover its condensed heterochromatic state rapidly before mitosis.…”

Section: Journal Of Cell Science 119 (12)mentioning

confidence: 99%

PML nuclear bodies are highly organised DNA-protein structures with a function in heterochromatin remodelling at the G2 phase

Luciani

Depétris

Usson

et al. 2006

Journal of Cell Science

119

106

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We have recently demonstrated that heterochromatin HP1 proteins are aberrantly distributed in lymphocytes of patients with immunodeficiency, centromeric instability and facial dysmorphy (ICF) syndrome. The three HP1 proteins accumulate in one giant body over the 1qh and 16qh juxtacentromeric heterochromatins, which are hypomethylated in ICF. The presence of PML (promyelocytic leukaemia) protein within this body suggests it to be a giant PML nuclear body (PML-NB). The structural integrity of PML-NBs is of major importance for normal cell functioning. Nevertheless, the structural organisation and the functions of these nuclear bodies remain unclear. Here, we take advantage of the large size of the giant body to demonstrate that it contains a core of satellite DNA with proteins being organised in ordered concentric layers forming a sphere around it. We extend these results to normal PML-NBs and propose a model for the general organisation of these structures at the G2 phase. Moreover, based on the presence of satellite DNA and the proteins HP1, BRCA1, ATRX and DAXX within the PML-NBs, we propose that these structures have a specific function: the re-establishment of the condensed heterochromatic state on late-replicated satellite DNA. Our findings that chromatin-remodelling proteins fail to accumulate around satellite DNA in PML-deficient NB4 cells support a central role for PML protein in this cellular function.

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A direct demonstration of somatically paired heterochromatin of human chromosomes

Cited by 102 publications

References 5 publications

DNA methylation and genetic instability in colorectal cancer cells

DNA methylation and genetic instability in colorectal cancer cells

Experimental condensation inhibition in constitutive and facultative heterochromatin of mammalian chromosomes

PML nuclear bodies are highly organised DNA-protein structures with a function in heterochromatin remodelling at the G2 phase

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