Interphase Chromosome Behavior in Normal and Diseased Cells

Bourne, Gemma; Moir, Catherine A.; Bikkul, Ural; Ahmed, Mai Hassan; Kill, Ian R.; Eskiw, Christopher H.; Tosi, Sabrina; Bridger, Joanna M.

doi:10.1007/978-1-4614-6558-4_2

Cited by 12 publications

(16 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We believe that the nuclear motors require nuclear envelope proteins such as emerin and the lamins to function correctly [ 48 ]. These genes will meet other genes at the transcription factories, and if this movement, co-occupation, transcription, and the return of the gene to its original location is not functioning correctly, then it is possible that chromosomal translocations are formed that are a hallmark of cancer [ 44 ].…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

The Non-random Repositioning of Whole Chromosomes and Individual Gene Loci in Interphase Nuclei and Its Relevance in Disease, Infection, Aging, and Cancer

Bridger¹,

Arican-Gotkas²,

Foster³

et al. 2014

Cancer Biology and the Nuclear Envelope

Self Cite

View full text Add to dashboard Cite

The genomes of a wide range of different organisms are non-randomly organized within interphase nuclei. Chromosomes and genes can be moved rapidly, with direction, to new non-random locations within nuclei upon a stimulus such as a signal to initiate differentiation, quiescence or senescence, or also the application of heat or an infection with a pathogen. It is now becoming increasingly obvious that chromosome and gene position can be altered in diseases such as cancer and other syndromes that are affected by changes to nuclear architecture such as the laminopathies. This repositioning seems to affect gene expression in these cells and may play a role in progression of the disease. We have some evidence in breast cancer cells and in the premature aging disease Hutchinson-Gilford Progeria that an aberrant nuclear envelope may lead to genome repositioning and correction of these nuclear envelope defects can restore proper gene positioning and expression in both disease situations.Although spatial positioning of the genome probably does not entirely control expression of genes, it appears that spatio-epigenetics may enhance the control over gene expression globally and/or is deeply involved in regulating specific sets of genes. A deviation from normal spatial positioning of the genome for a particular cell type could lead to changes that affect the future health of the cell or even an individual.

show abstract

Section: Discussionmentioning

confidence: 98%

“…Other studies only look at nuclear structure changes with respect to cancer and do not look at any genome behavioral changes [ 44 ]. Changing the nuclear architecture will have a direct effect on the genomes' stability and may then lead to cancer.…”

Section: Alterations To Genome Organization In Cancermentioning

confidence: 98%

The Non-random Repositioning of Whole Chromosomes and Individual Gene Loci in Interphase Nuclei and Its Relevance in Disease, Infection, Aging, and Cancer

Bridger¹,

Arican-Gotkas²,

Foster³

et al. 2014

Cancer Biology and the Nuclear Envelope

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, recent observations demonstrating relocation of activated genes with nuclear structures involved in transcription (e.g. RNA polymerase II molecules and Cajal bodies) provides further support for this hypothesis [21]. Whether genome organization determines function or whether localization is a “reflection” of function continues to be debated.…”

Section: Introductionmentioning

confidence: 99%

Spatial Positioning of All 24 Chromosomes in the Lymphocytes of Six Subjects: Evidence of Reproducible Positioning and Spatial Repositioning following DNA Damage with Hydrogen Peroxide and Ultraviolet B

et al. 2015

View full text Add to dashboard Cite

The higher-order organization of chromatin is well-established, with chromosomes occupying distinct positions within the interphase nucleus. Chromatin is susceptible to, and constantly assaulted by both endogenous and exogenous threats. However, the effects of DNA damage on the spatial topology of chromosomes are hitherto, poorly understood. This study investigates the organization of all 24 human chromosomes in lymphocytes from six individuals prior to- and following in-vitro exposure to genotoxic agents: hydrogen peroxide and ultraviolet B. This study is the first to report reproducible distinct hierarchical radial organization of chromosomes with little inter-individual differences between subjects. Perturbed nuclear organization was observed following genotoxic exposure for both agents; however a greater effect was observed for hydrogen peroxide including: 1) More peripheral radial organization; 2) Alterations in the global distribution of chromosomes; and 3) More events of chromosome repositioning (18 events involving 10 chromosomes vs. 11 events involving 9 chromosomes for hydrogen peroxide and ultraviolet B respectively). Evidence is provided of chromosome repositioning and altered nuclear organization following in-vitro exposure to genotoxic agents, with notable differences observed between the two investigated agents. Repositioning of chromosomes following genotoxicity involved recurrent chromosomes and is most likely part of the genomes inherent response to DNA damage. The variances in nuclear organization observed between the two agents likely reflects differences in mobility and/or decondensation of chromatin as a result of differences in the type of DNA damage induced, chromatin regions targeted, and DNA repair mechanisms.

show abstract

“…As all of the chromosome positioning was performed on proliferating cells, positive for Ki67, no cells that were either senescent or quiescent could have been analyzed. Therefore, the reactivation of telomerase in cancer cells could be responsible for changes of specific chromosome positioning (for overview see : especially of chromosome 18 and the subsequent consequences of genome reorganization). Consequently, this finding that chromosomes are repositioned in interphase is a concerning finding and has implications both for carcinogenesis and for hTERT‐immortalized cells being used for modeling in vivo conditions.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that exogenous telomerase will target the shorter telomeres in preference. 18,19 Indeed, chromosome and gene positioning in interphase nuclei is often altered in cancer cells [20][21][22][23][24] possibly through changes at the epigenomic level, telomere repositioning and/or anchorage to structures within the nucleoskeleton. 20,25 Chromosome territories [26][27][28] are nonrandomly positioned in cells 20,29,30 with distinct differences evident between cells in different proliferative states.…”

Section: Introductionmentioning

confidence: 99%

Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson‐Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform

Bikkul

Faragher

Worthington

et al. 2019

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

Immortalizing primary cells with human telomerase reverse transcriptase (hTERT) has been common practice to enable primary cells to be of extended use in the laboratory because they avoid replicative senescence. Studying exogenously expressed hTERT in cells also affords scientists models of early carcinogenesis and telomere behavior. Control and the premature ageing disease—Hutchinson‐Gilford progeria syndrome (HGPS) primary dermal fibroblasts, with and without the classical G608G mutation have been immortalized with exogenous hTERT. However, hTERT immortalization surprisingly elicits genome reorganization not only in disease cells but also in the normal control cells, such that whole chromosome territories normally located at the nuclear periphery in proliferating fibroblasts become mislocalized in the nuclear interior. This includes chromosome 18 in the control fibroblasts and both chromosomes 18 and X in HGPS cells, which physically express an isoform of the LINC complex protein SUN1 that has previously only been theoretical. Additionally, this HGPS cell line has also become genomically unstable and has a tetraploid karyotype, which could be due to the novel SUN1 isoform. Long‐term treatment with the hTERT inhibitor BIBR1532 enabled the reduction of telomere length in the immortalized cells and resulted that these mislocalized internal chromosomes to be located at the nuclear periphery, as assessed in actively proliferating cells. Taken together, these findings reveal that elongated telomeres lead to dramatic chromosome mislocalization, which can be restored with a drug treatment that results in telomere reshortening and that a novel SUN1 isoform combined with elongated telomeres leads to genomic instability. Thus, care should be taken when interpreting data from genomic studies in hTERT‐immortalized cell lines.

show abstract

Interphase Chromosome Behavior in Normal and Diseased Cells

Cited by 12 publications

References 120 publications

The Non-random Repositioning of Whole Chromosomes and Individual Gene Loci in Interphase Nuclei and Its Relevance in Disease, Infection, Aging, and Cancer

The Non-random Repositioning of Whole Chromosomes and Individual Gene Loci in Interphase Nuclei and Its Relevance in Disease, Infection, Aging, and Cancer

Spatial Positioning of All 24 Chromosomes in the Lymphocytes of Six Subjects: Evidence of Reproducible Positioning and Spatial Repositioning following DNA Damage with Hydrogen Peroxide and Ultraviolet B

Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson‐Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform

Contact Info

Product

Resources

About