Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer
Beatrice Rondinelli, Dalia Rosano, Elena Antonini, Michela Frenquelli, Laura Montanini, DaChuan Huang, Simona Segalla, Kosuke Yoshihara, Samir B. Amin, Dejan Lazarevic, Bin Tean The, Roel G.W. Verhaak, P. Andrew Futreal, Luciano Di Croce, Lynda Chin, Davide Cittaro, Giovanni Tonon
Beatrice Rondinelli, Dalia Rosano, Elena Antonini, Michela Frenquelli, Laura Montanini, DaChuan Huang, Simona Segalla, Kosuke Yoshihara, Samir B. Amin, Dejan Lazarevic, Bin Tean The, Roel G.W. Verhaak, P. Andrew Futreal, Luciano Di Croce, Lynda Chin, Davide Cittaro, Giovanni Tonon
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Research Article Genetics Oncology

Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer

Abstract

Mutations in genes encoding chromatin-remodeling proteins are often identified in a variety of cancers. For example, the histone demethylase JARID1C is frequently inactivated in patients with clear cell renal cell carcinoma (ccRCC); however, it is largely unknown how JARID1C dysfunction promotes cancer. Here, we determined that JARID1C binds broadly to chromatin domains characterized by the trimethylation of lysine 9 (H3K9me3), which is a histone mark enriched in heterochromatin. Moreover, we found that JARID1C localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with established players of heterochromatin assembly, including SUV39H1 and HP1α, as well as with proteins not previously associated with heterochromatin assembly, such as the cullin 4 (CUL4) complex adaptor protein DDB1. Transcription on heterochromatin is tightly suppressed to safeguard the genome, and in ccRCC cells, JARID1C inactivation led to the unrestrained expression of heterochromatic noncoding RNAs (ncRNAs) that in turn triggered genomic instability. Moreover, ccRCC patients harboring JARID1C mutations exhibited aberrant ncRNA expression and increased genomic rearrangements compared with ccRCC patients with tumors endowed with other genetic lesions. Together, these data suggest that inactivation of JARID1C in renal cancer leads to heterochromatin disruption, genomic rearrangement, and aggressive ccRCCs. Moreover, our results shed light on a mechanism that underlies genomic instability in sporadic cancers.

Authors

Beatrice Rondinelli, Dalia Rosano, Elena Antonini, Michela Frenquelli, Laura Montanini, DaChuan Huang, Simona Segalla, Kosuke Yoshihara, Samir B. Amin, Dejan Lazarevic, Bin Tean The, Roel G.W. Verhaak, P. Andrew Futreal, Luciano Di Croce, Lynda Chin, Davide Cittaro, Giovanni Tonon

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Figure 2

JARID1C contributes to heterochromatin maintenance and directly binds to satellite repeats during heterochromatin duplication.

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JARID1C contributes to heterochromatin maintenance and directly binds to...
(A) JARID1C downregulation reduces the average number and increases the size of chromocenters per cell. Representative confocal DAPI images of interphase NIH-3T3 transfected with scrambled (CTRsh) or JARID1C-specific (J1CshA/B) shRNAs. (B) DAPI-stained nuclear foci per cell were counted and their average area assessed (square pixels × 105 ). Data shown are from 1 of 3 experimental replicates. **P < 0.01 and ***P < 0.0001, 1-way ANOVA, with Tukey’s multiple comparisons test. (C) Representative immunofluorescence images of NIH-3T3 cells stained for DAPI and BrdU. Typical early, middle, and late S–phase patterns are shown. (D) Pie charts showing quantitative analysis of the proportion of S-phase cells in early, middle, and late S phase following transfection with control shRNA or shRNA against JARID1C. S-phase patterns were scored by BrdU patterns as shown in D. Data shown are from 1 of 2 experimental replicates (n = 150 S-phase nuclei per experiment). P < 0.001, Pearson’s χ2 test over the distribution. (E) Confocal immunofluorescence images of BrdU+ NIH-3T3 cells transfected with JARID1C-FLAG. J1C represents the signal obtained with anti-FLAG Ab.