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Differential distribution of HP1 proteins after trichostatin a treatment influences chromosomal stability in HCT116 and WI-38 cells

González-Barrios R, Soto-Reyes E, Quiroz-Baez R, Fabián-Morales E, Díaz-Chávez J, del Castillo V, Mendoza J, López-Saavedra A, Castro C, Herrera LA

Abstract Background Heterochromatin protein 1 (HP1) is important in the establishment, propagation, and maintenance of constitutive heterochromatin, especi ally at the pericentromeric region. HP1 might participate in recruiting and directing Mis12 to the centromere during interphase, and HP1 disruption or abrogation might lead to the loss of Mis12 incorporation into the kinetochore. Therefore, the centromere structure an d kinetochore relaxation that are promoted in the absence of Mis12 could further induce chromo some instability (CIN) by reducing the capacity of the kinetochore to anchor microtubules. The aim of this study was to determine whether alterations in the localization of HP1 prot eins induced by trichostatin A (TSA) modify Mis12 and Centromere Protein A (CENP-A) recr uitment to the centromere and whether changes in the expression of HP1 proteins a nd H3K9 methylation at centromeric chromatin increase CIN in HCT116 and WI-38 cells. Methods HCT116 and WI-38 cells were cultured and treated wi th TSA to evaluate CIN after 24 and 48 h of exposure. Immunofluorescence, Western blot, Ch IP, and RT-PCR assays were performed in both cell lines to evaluate the locali zation and abundance of HP1 α / β , Mis12, and CENP-A and to evaluate chromatin modifications during interphase and mitosis, as well as after 24 and 48 h of TSA treatment. Results Our results show that the TSA-induced reduction in heterochromatic histone marks on centromeric chromatin reduced HP1 at the centromere in the non-tumoral WI-38 cells and that this reduction was associated with cell cycle arrest and CIN. However, in HCT116 cells, HP1 proteins, together with MIS12 and CENP-A, reloc ated to centromeric chromatin in response to TSA treatment, even after H3K9me3 deple tion in the centromeric nucleosomes. The enrichment of HP1 and the loss of H3K9me3 were associated with an increase in CIN, suggesting a response mechanism at centromeric and pericentromeric chromatin that augments the presence of HP1 proteins in those regi ons, possibly ensuring chromosome segregation despite serious CIN. Our results provid e new insight into the epigenetic landscape of centromeric chromatin and the role of HP1 proteins in CIN.


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December, 2014



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