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Preferential localization of γH2AX foci in euchromatin of retina rod cells after DNA damage induction

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Abstract

DNA damage may lead to cell transformation, senescence, or death. Histone H2AX phosphorylation, immunodetected as γH2AX foci, is an early response to DNA damage persisting even after DNA repair. In cycling mammalian cells with canonical nuclear architecture, i.e., central euchromatin and peripheral heterochromatin, γH2AX foci map preferentially to euchromatin. Mice retina rods are G0 cells displaying an inverted nuclear architecture 28 days after birth (P28). Rod nuclei exhibit one or two central constitutive heterochromatin chromocenters encircled by facultative heterochromatin. Euchromatin resides at the nuclear periphery, extending to the equator in cells with two chromocenters. To assess the impact of chromatin relocation in the localization of DNA damage, γH2AX and TUNEL foci induced ex vivo by radiomimetic bleomycin were mapped in H3K4me3 immunolabeled P28 rod nuclei. A preferential localization of γH2AX foci in euchromatin was detected together with foci clustering. Besides, a decay of H3K4me3 signal at γH2AX foci sites was observed. TUNEL and γH2AX foci exhibited similar localization patterns in BLM-treated rod cells thus excluding curtailed access of anti-γH2AX antibodies to heterochromatin. Lack of γH2AX foci in rod chromocenters appears to be unrelated to the occurrence of mid-range foci movements. Foci clusters may arise through DNA double-strand break proximity, local non-directional chromatin movements or chromatin relaxation. H3K4me3 signal reduction at γH2AX foci could stem from local chromatin decondensation or downregulation of histone H4 methylation. The observed topology of DNA damage in retina-differentiated rods indicates that euchromatin is damage-prone, regardless of the canonical or inverted nuclear architecture of mammalian cells.

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Abbreviations

γH2AX:

Histone H2AX phosphorylated on serine 139

APP:

Amyloid precursor protein

ATM:

Ataxia Telangiectasia Mutated

ATR:

Ataxia Telangiectasia Related

BLM:

Bleomycin

CA:

Chromosomal aberrations

DNA-PK:

DNA-dependent Protein Kinase

DSB:

DNA double-strand break

E-64:

trans-Epoxysuccinyl-l-leucylamido-(4-guanidino) butane

EDDI:

Euchromatic damage distribution index

GCL:

Retina ganglion cell layer

H3K4me3:

Histone H3 trimethylated on lysine 4

INL:

Retina inner nuclear layer

LM/ESI:

Correlative light microscopy and electron spectroscopic imaging

MHC I:

Major histocompatibility complex

NPHR:

Non-photoreceptor cells

ONL:

Retina outer nuclear layer

P28:

Twenty-eight days after birth

PHR:

Photoreceptor cells

RIDGES:

Regions of increased gene expression

ROI:

Region of interest

SSB:

DNA single-strand break

Tdt:

Terminal deoxynucleotidyl-transferase

TSS:

Transcriptional start site

TUNEL:

Terminal deoxynucleotidyl-transferase dUTP nick end labeling

UV-C:

Ultraviolet light

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Acknowledgments

We are indebted to Omar Trujillo for technical advice regarding retina dissection and to Thomas and Marion Cremer and Ricardo Benavente for helpful suggestions on the manuscript. We also wish to thank Cristina Arrutti for stimulating discussions. The work was financed in part by the Programa de Desarrollo en Ciencias Básicas (PEDECIBA, Uruguay) and the Agencia Nacional de Investigación e Innovación (ANII).

Conflict of interest

Laura Lafon-Hughes, María Vittoria Di Tomaso, Pablo Liddle, Andrea Toledo, Ana Laura Reyes-Ábalos, and Gustavo A. Folle declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departamento de Genética, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay

    Laura Lafon-Hughes, María Vittoria Di Tomaso, Pablo Liddle, Ana Laura Reyes-Ábalos & Gustavo A. Folle

  2. Departamento de Biología Celular y Molecular, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay

    Andrea Toledo

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  1. Laura Lafon-Hughes
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  2. María Vittoria Di Tomaso
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  3. Pablo Liddle
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Correspondence to Laura Lafon-Hughes.

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Supplementary Figure 1

Comparison of CHO-AA8 and mice retina sensitivity to BLM (160). AA8 and retinas were treated in parallel with 160 μM BLM for 1 h. Then, they were fixed in 4 % PFA, immunolabelled for γH2AX (red) and counterstained with DAPI (blue). Left: CHO cells; right: mice retina. Confocal images (×40). Bars 10 μm and 5 μm, respectively. (JPEG 67 kb)

High resolution image (TIFF 2508 kb)

Supplementary Figure 2

(A) Retina outer nuclear layer (ONL) overview. Absent or extremely rare H2AX phosphorylation is observed, except in cotreated (E64 + BLM) retinas. γH2AX (red) and DAPI (blue) signals are shown. Bar 5 μm. (B) Image gallery: preliminary analysis of γH2AX foci distribution in rare γH2AX + photoreceptors detected in different mice and BLM treatments. Green: γH2AX mask. A red mask representative of heterochromatin was created by thresholding DAPI channel images. Besides, DAPI channel was saturated to permit a better visualization of euchromatin. The resulting merged image allows a rough visualization of central constitutive heterochromatin (pink), facultative heterochromatin (red), and euchromatin (blue). CHc constitutive heterochromatin, FHc facultative heterochromatin, Ec euchromatin. Bar 5 μm. (JPEG 142 kb)

High resolution image (TIFF 3779 kb)

Supplementary Figure 3

Confocal images of 10 μM E-64-treated and 10 μM E-64 (4 h) + 80 μM BLM (3 h)-treated retinas ONL. γH2AX foci (red), H3K4me3 (green), and DAPI (blue) signals are depicted. DNA damage is evident in the BLM-treated retina. Bar 5 μm. (JPEG 108 kb)

High resolution image (TIFF 3311 kb)

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Lafon-Hughes, L., Di Tomaso, M.V., Liddle, P. et al. Preferential localization of γH2AX foci in euchromatin of retina rod cells after DNA damage induction. Chromosome Res 21, 789–803 (2013). https://doi.org/10.1007/s10577-013-9395-3

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