Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer
Beatrice Rondinelli, … , Davide Cittaro, Giovanni Tonon
Beatrice Rondinelli, … , Davide Cittaro, Giovanni Tonon
Published November 9, 2015
Citation Information: J Clin Invest. 2015;125(12):4625-4637. https://doi.org/10.1172/JCI81040.
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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 1

Co-occurrence of JARID1C and heterochromatin.

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Co-occurrence of JARID1C and heterochromatin. (A) Snapshot of representa...
(A) Snapshot of representative genomic region showing the co-occupancy of JARID1C and H3K9me3 ChIP-seq profiles. Two different Abs were used for the JARID1C (Ab1, Abcam; Ab2, Bethyl Laboratories) and H3K9me3 (Ab1, EMD Millipore; Ab2, Abcam) IP experiments. Each track represents an overlay of 2 independent replicates. chr1, chromosome 1. (B) Hilbert curve representation of multiple ChIP-seq profiles on chromosome 2. Multiple markers were assigned to the color channel before merging (JARID1C, yellow; H3K9me3, magenta; H3K4me1, cyan; H3K4me3, gray). Merged image is annotated with both telomere positions (pT, short arm; qT, long arm) and the centromere (c); a map of chromosome positions is also presented in the bottom left panel. (C) Heatmap showing the correlation between the multiple ChIP-seq signals discussed in the main text. Correlation values were used to generate dendrograms. (D) ChIP with anti-JARID1C Ab specific to the human protein in Caki-1 renal cancer cells. ChIP was analyzed by qPCR with primers for BDNF, a known promoter of binding sites for JARID1C (45), chrom 1 and chrom 4 αSAT (centric satellites of chromosomes 1 and 4), and SAT2 and pericentric SATα, pericentric satellites of human chromosomes. Results are expressed as the percentage of input. Error bars represent the SEM of 3 independent experiments. *P < 0.05, **P < 0.01, Student’s t test.