Abstract
Inborn defects in DNA repair are associated with complex developmental disorders whose causal mechanisms are poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the nucleotide excision repair (NER) structure-specific endonuclease ERCC1–XPF complex interacts with the insulator binding protein CTCF, the cohesin subunits SMC1A and SMC3 and with MBD2; the factors co-localize with ATRX at the promoters and control regions (ICRs) of imprinted genes during postnatal hepatic development. Loss of Ercc1 or exposure to MMC triggers the localization of CTCF to heterochromatin, the dissociation of the CTCF–cohesin complex and ATRX from promoters and ICRs, altered histone marks and the aberrant developmental expression of imprinted genes without altering DNA methylation. We propose that ERCC1–XPF cooperates with CTCF and cohesin to facilitate the developmental silencing of imprinted genes and that persistent DNA damage triggers chromatin changes that affect gene expression programs associated with NER disorders.
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Acknowledgements
The THALIS ESPA 2007–2013 ‘GenAge’ (MIS380228) and ‘miREG’ (MIS380247), the ARISTEIA ‘TagNER’ (45) and ‘Epilogeas’ (3446), the FP7 Marie Curie ITN ‘aDDRess (GA316390), ‘CodeAge’ (GA316354), ‘Marriage’ (GA316964) and ‘Chromatin3D (GA622934), and the Horizon 2020 ERC Consolidator grant ‘DeFiNER’ (GA64663) supported this work. G.A.G. was supported by the EMBO Young Investigator programme. I.K. was supported by the Maria-Michail Manassakis fellowship. We thank M. Fousteri for providing the reagents for the unscheduled DNA synthesis assay and the Fanconi Anemia Research Fund (FA Cell Repository and the FA Antibody Project) for anti-FANCA and anti-FANCD2 antibodies and corresponding mutant MEFs.
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G.C., Z.A., T.A.-P., A.I., M.T., M.A., I.K. and T.K. performed the experiments and analysed data. T.K., G.L.P. and J.S. generated new reagents. G.A.G. interpreted data and wrote the manuscript. All relevant data are available from the authors.
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Integrated supplementary information
Supplementary Figure 1 Ablation of Ercc1 gene triggers the aberrant silencing of imprinted genes during postnatal hepatic development.
(A) Schematic representation of transgenic mice expressing the BirA biotin ligase transgene and anti-HA immunoblot showing expression of the BirA biotin ligase protein in different tissues of 2-month old BirA transgenic animals (as indicated). (B) Streptavidin pull-downs in nuclear or chromatin extracts under native (micrococcal nuclease digested) conditions derived from primary bXPF MEFs expressing the BirA transgene or the BirA transgenic animals (as indicated) and analysed by Western blotting for CTCF. (C) Over-represented biological processes derived from the significantly aberrantly expressed imprinted genes in P15 Ercc1−/− compared to age-matched wt livers; p : -log of P-value which is calculated by Fisher’s exact test right-tailed. Red dotted line marks the threshold of significance at 0.05. (D) qPCR mRNA levels of imprinted genes in P15 Ercc1−/− spleen, kidney, white adipose tissue (WAT), pancreas and cerebellum (as indicated; n = 3 biological replicates each representing a pool of 4-5 tissues/genotype). Red dotted line: wt mRNA levels. Error bars indicate s.d.; two tailed t-test. Statistical source data are provided in Supplementary Table 6.
Supplementary Figure 2 DNA methylation at the Igf2, Peg3, Dlk1 and Peg3 proximal promoter regions in Ercc1−/− livers.
(A) ChIP-seq profiles marking the recruitment of CTCF and RNAPII (Pol2) at the H19, Dlk1, Peg3 and Grb10 promoter and ICRs/DMR regions in livers (liv) or mouse embryonic fibroblasts (MEFs) as indicated. Arrow heads mark the PCR amplified ICR or promoter (prom) regions (as indicated). (B–G) Schematic representation of the% of DNA methylation at the Peg3 (promoter), Grb10 (CTCF-peak), Igf2 (promoter 2 and 3), Grb10 (promoter) and Meg3 (ICR) regions (as indicated) in P15 Ercc1−/− and wt livers. Black circles: methylated cytosine; open circles: unmethylated cytosine.
Supplementary Figure 3 Dissociation of the CTCF-cohesin complex and MBD2 from the promoters and ICRs of imprinted genes in Ercc1−/− livers.
(A) bXPF, CTCF, SMC1A, SMC3, MBD2 and ATRX ChIP signals expressed as fold enrichment over those obtained with BirA (for bXPF) or control antibody (IgG) at the Igf2, Peg3, Dlk1 and Grb10 promoters in P15 wt mouse livers (as indicated; n = 3 biological replicates each representing a pool of 4–5 livers). Error bars indicate s.e.m. among replicates (n ≥ 3). (B) ChIP signals shown as % of input of CTCF, SMC1A, SMC3, MBD2 and ATRX at the Igf2, Peg3, Meg3 and Grb10 ICR regions and CTCF negative (-) regions (as indicated; n = 3 biological replicates each representing a pool of 4–5 livers). Error bars indicate s.e.m. (C) CTCF, SMC1A, SMC3, MBD2 and ATRX ChIP signals normalized against their respective control antibody (IgG) and expressed as fold enrichment over the corresponding ChIP signals obtained for wt mouse livers at the Dlk1/Meg3 and Grb10 promoters and ICRs (as indicated; n = 3 biological replicates each representing a pool of 4–5 livers). Error bars indicate s.e.m., ∗:P ≤ 0.05; two-tailed t-test. Statistical source data are provided in Supplementary Table 6.
Supplementary Figure 4 Persistent DNA ICLs trigger aberrant CTCF and ATRX localization in Ercc1−/− and MMC-treated MEFs.
(A) Immunofluorescence detection of CTCF in Csbm/m primary mouse embryonic fibroblasts (MEFs; 20 fields analysed from 3 biological replicates). (B) Equal amount of nuclear extracts from wt, MMC-treated and Ercc1−/− MEFs analysed by Western blotting for CTCF, SMC1A and TBP. (C) Immunocolocalization of CTCF and HP1a in MMC-treated and untreated P4 MEFs. (D) Immunofluorescence detection of ATRX in Ercc1−/−, Csbm/m, Xpc−/− and Xpa−/− primary mouse embryonic fibroblasts (MEFs; 20 fields analysed from 3 biological replicates). Note the distinctive accumulation of ATRX to heterochromatin in Ercc1−/− MEFs. (E) Immunofluorescence detection of SMC1A in primary Csbm/m MEFs. (F) Immunofluorescence detection of SMC3 in wt, Ercc1−/−, Csbm/m, Xpc−/− and Xpa−/−primary MEFs (as indicated; 20 fields analysed from 3 biological replicates). (G–H). Immunofluorescence detection of CTCF and ATRX in primary wt and Ercc1−/− hepatocytes; note the distinctive translocation of CTCF and accumulation of ATRX to heterochromatin Ercc1−/− hepatocytes. (I). Immunofluorescence detection of γH2aX and nucleolin in wt and Ercc1−/− MEFs (upper panel) and in MMC-treated and untreated control (ctrl) MEFs (lower panel); the graph depicts the average number of γH2aX-positive stained cells in wt and Ercc1−/− MEFs or wt MEFs exposed to MMC from 20 fields analysed representing n = 3 biological replicates∗: P-value ≤ 0.05. (J) Immunocolocalization of CTCF and γH2aX in MMC-treated and untreated P4 MEFs. Scale bars, 5 μm. Statistical source data are provided in Supplementary Table 6.
Supplementary Figure 5 Persistent DNA ICLs trigger aberrant CTCF and ATRX localization in Ercc1−/− and MMC-treated MEFs.
(A) Immunofluorescence detection of CTCF in serum starved (SS) MEFs exposed to MMC (as indicated; 20 fields analysed from 3 biological replicates). (B) Immunofluorescence detection of ATRX in primary MEFs exposed to MMC, UV and H2O2; Ctr: untreated MEFs. Note the distinctive accumulation of ATRX to heterochromatin in MMC-treated MEFs. (C) Immunocolocalization of CTCF and ATRX in MMC-treated primary P4 MEFs. (D) Co-immunoprecipitation experiments using αCTCF in nuclear extracts from P15 livers analysed by Western blotting for FANCA or FANCD2. (E) Immunofluorescence detection of CTCF in Fanca−/− and Fancd2−/− MEFs (as indicated; 20 fields analysed from 3 biological replicates). Scale bars, 5 μm.
Supplementary Figure 6 Persistent DNA ICLs trigger the dissociation of the CTCF-cohesin complex and MBD2 from promoters and ICRs.
(A). Quantitative (q) PCR mRNA levels of UV-responsive and imprinted genes in primary mouse dermal fibroblasts exposed to 0.6 and 4 J m−2 of UVC irradiation (as indicated), n = 3 biological replicates/dose. Error bars indicate s.d. (B). qPCR mRNA levels of H2O2-responsive and imprinted genes in primary mouse dermal fibroblasts treated with 10 μM or 50 μM of H2O2 (as indicated), n = 3 biological replicates/dose. Error bars indicate s.d. (C) ChIP signals of CTCF, SMC1A and SMC3 (as indicated) at the H19, Peg3, Dlk1 and Grb10 promoters in primary MEFs exposed to UV, H2O2 and MMC or to MMC and ATM or ATR inhibitors (ATMi, ATRi as indicated). ChIP signals from treated MEFs were normalized to respective control antibody (IgG) which were set as 1 (red dotted line) and expressed as fold enrichment over those obtained from untreated MEFs, n = 3 biological replicates. Error bars indicate s.d.; two-sided t-test. Statistical source data are provided in Supplementary Table 6.
Supplementary Figure 7 Persistent DNA ICLs trigger changes in histone marks associated with aberrant postnatal silencing.
(A) Allele-specific ChIP signals of CTCF, SMC1A and SMC3 (as indicated) at the H19 ICR in MMC-treated C57BL/6/SPRET/Eij MEFs (as indicated). ChIP signals expressed as fold enrichment over those obtained with control antibody (IgG). Error bars indicate s.d. among biological replicates; (n = 3 biological replicates). (B) ChIP signals of repressive H3K27me and H3K9me3 histone marks at the H19, Peg3, Dlk1 and Grb10 promoters in primary MEFs exposed to MMC, UV or H2O2 (as indicated) and in MMC-treated MEFs treated with ATMi or ATRi (as indicated). ChIP signals are shown as in Fig. 5c. To test for significance, ChIP signals of ATMi and ATRi-treated MEFs are compared against those of MMC-treated MEFs; two sided t-test. (C–D). ChIP signals of activating H3K9Ac and H3K4me3 histone marks at the H19/Igf2, Peg3, Meg3/Dlk1 and Grb10 ICRs and promoters in primary MEFs exposed to MMC, UV or H2O2 (as indicated) and in MMC-treated MEFs treated with ATMi or ATRi (as indicated; n = 3 biological replicates). ChIP signals are shown as in Fig. 5c. To test for significance, ChIP signals of MMC-treated MEFs are compared against untreated cells; ChIP signals of ATMi and ATRi-treated MEFs are compared against those of MMC-treated MEFs. ∗∗:P ≤ 0.01, Error bars indicate s.d.; two-sided t-test. Statistical source data are provided in Supplementary Table 6.
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Chatzinikolaou, G., Apostolou, Z., Aid-Pavlidis, T. et al. ERCC1–XPF cooperates with CTCF and cohesin to facilitate the developmental silencing of imprinted genes. Nat Cell Biol 19, 421–432 (2017). https://doi.org/10.1038/ncb3499
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DOI: https://doi.org/10.1038/ncb3499
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