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Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains

Finding out how cells prepare for fate change during differentiation commitment was our task. To address whether the constitutive pericentromere-associated domains (PADs) may be involved, we used a model system with known transcriptome data, MCF-7 breast cancer cells treated with the ErbB3 ligand he...

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Autores principales: Krigerts, Jekabs, Salmina, Kristine, Freivalds, Talivaldis, Zayakin, Pawel, Rumnieks, Felikss, Inashkina, Inna, Giuliani, Alessandro, Hausmann, Michael, Erenpreisa, Jekaterina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Biophysical Society 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896032/
https://www.ncbi.nlm.nih.gov/pubmed/33453273
http://dx.doi.org/10.1016/j.bpj.2021.01.002
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author Krigerts, Jekabs
Salmina, Kristine
Freivalds, Talivaldis
Zayakin, Pawel
Rumnieks, Felikss
Inashkina, Inna
Giuliani, Alessandro
Hausmann, Michael
Erenpreisa, Jekaterina
author_facet Krigerts, Jekabs
Salmina, Kristine
Freivalds, Talivaldis
Zayakin, Pawel
Rumnieks, Felikss
Inashkina, Inna
Giuliani, Alessandro
Hausmann, Michael
Erenpreisa, Jekaterina
author_sort Krigerts, Jekabs
collection PubMed
description Finding out how cells prepare for fate change during differentiation commitment was our task. To address whether the constitutive pericentromere-associated domains (PADs) may be involved, we used a model system with known transcriptome data, MCF-7 breast cancer cells treated with the ErbB3 ligand heregulin (HRG), which induces differentiation and is used in the therapy of cancer. PAD-repressive heterochromatin (H3K9me3), centromere-associated-protein-specific, and active euchromatin (H3K4me3) antibodies, real-time PCR, acridine orange DNA structural test (AOT), and microscopic image analysis were applied. We found a two-step DNA unfolding after 15–20 and 60 min of HRG treatment, respectively. This behavior was consistent with biphasic activation of the early response genes (c-fos - fosL1/myc) and the timing of two transcriptome avalanches reported in the literature. In control, the average number of PADs negatively correlated with their size by scale-free distribution, and centromere clustering in turn correlated with PAD size, both indicating that PADs may create and modulate a suprachromosomal network by fusing and splitting a constant proportion of the constitutive heterochromatin. By 15 min of HRG treatment, the bursting unraveling of PADs from the nucleolus boundary occurred, coinciding with the first step of H3K4me3 chromatin unfolding, confirmed by AOT. The second step after 60 min of HRG treatment was associated with transcription of long noncoding RNA from PADs and peaking of fosL1/c-myc response. We hypothesize that the bursting of PAD clusters under a critical silencing threshold pushes the first transcription avalanche, whereas the destruction of the PAD network enables genome rewiring needed for differentiation repatterning, mediated by early response bivalent genes.
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spelling pubmed-78960322022-02-16 Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains Krigerts, Jekabs Salmina, Kristine Freivalds, Talivaldis Zayakin, Pawel Rumnieks, Felikss Inashkina, Inna Giuliani, Alessandro Hausmann, Michael Erenpreisa, Jekaterina Biophys J Articles Finding out how cells prepare for fate change during differentiation commitment was our task. To address whether the constitutive pericentromere-associated domains (PADs) may be involved, we used a model system with known transcriptome data, MCF-7 breast cancer cells treated with the ErbB3 ligand heregulin (HRG), which induces differentiation and is used in the therapy of cancer. PAD-repressive heterochromatin (H3K9me3), centromere-associated-protein-specific, and active euchromatin (H3K4me3) antibodies, real-time PCR, acridine orange DNA structural test (AOT), and microscopic image analysis were applied. We found a two-step DNA unfolding after 15–20 and 60 min of HRG treatment, respectively. This behavior was consistent with biphasic activation of the early response genes (c-fos - fosL1/myc) and the timing of two transcriptome avalanches reported in the literature. In control, the average number of PADs negatively correlated with their size by scale-free distribution, and centromere clustering in turn correlated with PAD size, both indicating that PADs may create and modulate a suprachromosomal network by fusing and splitting a constant proportion of the constitutive heterochromatin. By 15 min of HRG treatment, the bursting unraveling of PADs from the nucleolus boundary occurred, coinciding with the first step of H3K4me3 chromatin unfolding, confirmed by AOT. The second step after 60 min of HRG treatment was associated with transcription of long noncoding RNA from PADs and peaking of fosL1/c-myc response. We hypothesize that the bursting of PAD clusters under a critical silencing threshold pushes the first transcription avalanche, whereas the destruction of the PAD network enables genome rewiring needed for differentiation repatterning, mediated by early response bivalent genes. The Biophysical Society 2021-02-16 2021-01-14 /pmc/articles/PMC7896032/ /pubmed/33453273 http://dx.doi.org/10.1016/j.bpj.2021.01.002 Text en © 2021 Biophysical Society. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Articles
Krigerts, Jekabs
Salmina, Kristine
Freivalds, Talivaldis
Zayakin, Pawel
Rumnieks, Felikss
Inashkina, Inna
Giuliani, Alessandro
Hausmann, Michael
Erenpreisa, Jekaterina
Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains
title Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains
title_full Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains
title_fullStr Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains
title_full_unstemmed Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains
title_short Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains
title_sort differentiating cancer cells reveal early large-scale genome regulation by pericentric domains
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896032/
https://www.ncbi.nlm.nih.gov/pubmed/33453273
http://dx.doi.org/10.1016/j.bpj.2021.01.002
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