Modifications of nuclear architecture and chromatin organization in ataxia telangiectasia cells are coupled to changes of gene transcription.
Ataxia telangiectasia (AT) is a rare genetic disorder caused by mutations of ATM gene. ATM kinase is a "master controller" of DNA-damage response and signal transducer of external stimuli. The complex role of ATM may explain the pleiotropic phenotype characteristic of AT syndrome, only partially. In our hypothesis, the multi-faceted phenotype of AT patients might depend on specific chromatin reorganization, which then reflects on the cellular transcription. We analyzed three lymphoblastoid cell-lines isolated from AT patients and one healthy control. The three-dimensional reconstruction disclosed marked changes of nuclear morphology and architecture in AT cells. When chromatin condensation was analyzed by differential scanning calorimetry, a remodeling was observed at the level of fiber folding and nucleosome conformation. Despite the structural differences, chromatin did not exhibit modifications of the average acetylation status in comparison to the control. Moreover, AT cells presented significant alterations in the transcription of genes involved in cell-cycle regulation and stress response. In AT3RM cells, the average chromatin decondensation went with the upregulation of c-fos, c-jun, and c-myc and downregulation of metallothioneins, p21 and p53. AT9RM and AT44RM cells were instead characterized by an increased chromatin condensation and presented a different transcription unbalance. Whereas in AT44RM all the considered genes were downregulated, in AT3RM the three oncogenes and metallothioneins were upregulated, but p53 and p21 were downregulated.
Grattarola
Myriam
M
Department of Biophysical Sciences and Techologies M.&O.-Biophysical Division, University of Genova, Genova, Italy.
Borghi
Cristina
C
Emionite
Laura
L
Lulli
Patrizia
P
Chessa
Luciana
L
Vergani
Laura
L
D000107:Acetylation; D001260:Ataxia Telangiectasia / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D002846:Chromatography, Affinity; D004247:DNA / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008668:Metallothionein / Q000378:metabolism; D008968:Molecular Conformation; D009691:Nucleic Acid Denaturation; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D014158:Transcription, Genetic
D006657:Histones; D009707:Nucleosomes; D004247:DNA; D008668:Metallothionein