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The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy

Nature Medicine volume 22, pages 1131–1139 (2016)Cite this article

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Abstract

Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.

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Figure 1: Chaer regulates cardiac hypertrophy.
Figure 2: Chaer negatively regulates H3K27 trimethylation via its interaction with the catalytic subunit of PRC2.
Figure 3: Characterization of a Chaer motif that interacts with PRC2.
Figure 4: Transiently enhanced Chaer–PRC2 interaction regulates hypertrophic gene induction and targeted H3K27me3 modification.
Figure 5: mTORC1 signaling pathway mediates the EZH2–Chaer interaction after hypertrophic stimulation.
Figure 6: Chaer functions as an early checkpoint for TAC-induced hypertrophy in vivo.

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Acknowledgements

This work was supported in part by the US National Institute of Health (NIH) (grant no. HL070079 (Y.W.), HL103205 (Y.W.), HL108186 (Y.W.), HL110667 (Y.W.), HL115238 (T.M.V.), R01HG006264 (X.X.) and U01HG007013 (X.X.)), the University of California at Los Angeles CTSI–Cardiovascular Pilot Team research grant UL1TR000124 (Y.W., X.X. and T.M.V.), the National Science Fund for Distinguished Young Scholars (grant no. 81425005; H.L.), the Key Project of the National Natural Science Foundation (grant no. 81330005 and 81630011; both to H.L.), the National Science and Technology Support Project (grant no. 2013YQ030923-05, 2014BAI02B01 and 2015BAI08B01; all to H.L.) and an American Heart Association Western States Affiliate Postdoctoral Fellowship (15POST24970034; Z.W.). C.G. was a recipient of the UCLA Eli and Edythe Broad Center Predoctoral Fellowship in Stem Cell Science. H.W. was supported by the China Scholarship Council (award no. 201406280042) and was a recipient of a Jennifer S. Buchwald Graduate Fellowship in Physiology. A.C. was supported by NIH predoctoral training grant T90DE022734. The authors wish to acknowledge outstanding technical support from H. Pu and Core support from the UCLA Cardiovascular Research Laboratories and the Division of Molecular Medicine at UCLA.

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Zhihua Wang, Xiao-Jing Zhang, Yan-Xiao Ji, Peng Zhang, Ke-Qiong Deng, Jun Gong & Hongliang Li

  2. Animal Experiment Center–Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China

    Zhihua Wang, Xiao-Jing Zhang, Yan-Xiao Ji, Peng Zhang, Ke-Qiong Deng, Jun Gong & Hongliang Li

  3. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China

    Zhihua Wang, Xiao-Jing Zhang, Yan-Xiao Ji, Peng Zhang, Ke-Qiong Deng, Jun Gong & Hongliang Li

  4. Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA

    Zhihua Wang, Shuxun Ren, Iris Chen, He Wang, Chen Gao, Tomohiro Yokota, Thomas M Vondriska & Yibin Wang

  5. Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China

    Xinghua Wang & Guangping Li

  6. Gladstone Institute of Cardiovascular Diseases, San Francisco, California, USA

    Yen Sin Ang & Deepak Srivastava

  7. University of California, San Francisco, School of Medicine, San Francisco, California, USA

    Yen Sin Ang & Deepak Srivastava

  8. Department of Medicine, Cardiology Division, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA

    Shen Li, Arjun Deb & Yibin Wang

  9. Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA

    Shen Li, Arjun Deb & Yibin Wang

  10. Department of Integrative Biology and Physiology, College of Life Sciences, Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA

    Ashley Cass & Xinshu Xiao

  11. Bioinformatics Interdepartmental Program, University of California at Los Angeles, Los Angeles, California, USA

    Ashley Cass & Xinshu Xiao

  12. Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Huang-Tian Yang

  13. Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Huang-Tian Yang

  14. Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Huang-Tian Yang

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  1. Zhihua Wang
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Contributions

Z.W. designed all the experiments with input from H.-T.Y., H.L. and Y.W., performed the majority of the experiments and drafted the manuscript; Y.W. designed and supervised the study; H.L. designed and supervised the in vivo experiments; X.-J.Z., Y.-X.J., P.Z. and K.-Q.D. performed the northern blot, ChIP, FISH, immunoblotting and PV loop assays for Chaer-KO mice with input from H.L.; K.-Q.D., J.G. and H.L. developed the Chaer-knockout mice and performed some of the in vivo experiments; X.W. and G.L. participated in the tagged-RNA pulldown assay and RIP assays; I.C., C.G. and H.W. participated in the lncRNA screening and cloning experiments; T.Y. participated in the histology assay; A.C., X.X. and T.M.V. participated in the transcriptome analysis; S.R. performed the TAC surgery; Y.S.A. and D.S. provided the human iPSC-derived cardiomyocytes; S.L. and A.D. provided the primary cardiac fibroblasts and myocytes from mouse heart.

Corresponding authors

Correspondence to Hongliang Li or Yibin Wang.

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The authors declare no competing financial interests.

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Wang, Z., Zhang, XJ., Ji, YX. et al. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 22, 1131–1139 (2016). https://doi.org/10.1038/nm.4179

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