SummaryThe role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodeling. An estimated 70% of mouse genes undergo antisense transcription1, including myosin heavy chain 7 (Myh7) that encodes molecular motor proteins for heart contraction2. Here, we identify a cluster of lncRNA transcripts from Myh7 loci and show a new lncRNA–chromatin mechanism for heart failure. In mice, these transcripts, which we named Myosin Heavy Chain Associated RNA Transcripts (MyHEART or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex3 to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodeling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy3. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. Mhrt binds to the helicase domain of Brg1, and this domain is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized—but not naked—DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodeling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify the first cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodeling factors, and establish a new paradigm for lncRNA–chromatin interaction.

SUMMARYCardiac hypertrophy and failure are characterized by transcriptional reprogramming of gene expression. Adult cardiomyocytes in mice express primarily α-myosin heavy chain (α-MHC), whereas embryonic cardiomyocytes express β-MHC. Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from α-MHC to fetal β-MHC expression. Here we show that Brg1, a chromatin-remodeling protein, plays critical roles in regulating cardiac growth, differentiation and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining BMP10 and suppressing p57kip2 expression. It preserves fetal cardiac differentiation by interacting with HDAC and PARP to repress α-MHC and activate β-MHC. In adults, Brg1 is turned off in cardiomyocytes. It is reactivated by cardiac stresses and complexes with its embryonic partners, HDAC and PARP, to induce a pathological α- to β-MHC shift. Preventing Brg1 re-expression decreases hypertrophy and reverses such MHC switch. Brg1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Our studies show that Brg1 maintains cardiomyocytes in an embryonic state, and demonstrate an epigenetic mechanism by which three classes of chromatin-modifying factors, Brg1, HDAC and PARP, cooperate to control developmental and pathological gene expression.

Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen—Lysyl oxidase-like 2 (Loxl2)—is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.

Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.

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In this study, we recruited 49 subjects from one village close to an electronic waste (e-waste) site (exposed group) and another located 50 km away from the e-waste site (control group). We found that serum levels of polybrominated diphenyl ethers (median PBDEs, 382 ng/g lipid weight; range, 77-8452 ng/g lipid weight) and thyroid-stimulating hormone (median TSH, 1.79 microIU/mL; range, 0.38-9.03 microIU/mL) and frequencies of micro-nucleated binucleated cells (MNed BNC; median, 5% per hundred; range, 0-96% per hundred) were significantly higher in the exposed group than in the control group (158 ng/g, range of 18-436 ng/g, and p < 0.05; 1.15 microIU/mL, range of 0.48-2.09, and p < 0.01; and 0% per hundred, range of 0-5% per hundred, and p < 0.01, respectively). A history of working with e-waste was significantly associated with increased MNed BNC frequencies (odds ratio (OR), 38.85; 95% confidence interval (CI) = 1-1358.71, p = 0.044), independent of years of local residence, a perceived risk factor. However, there was no association between PBDEs exposure and oxidative DNA damage. Therefore, the exposure to PBDEs at the e-waste site may have an effect on the levels of TSH and genetoxic damage among these workers, but this needs to be validated in large studies.

The recently discovered human enzyme DNA polymerase (pol ) has been shown to have an exceptionally high error rate on artificial DNA templates. Although there is a considerable body of in vitro evidence for a role for pol in DNA lesion bypass, there is no in vivo evidence to confirm this action. We report here that pol expression is elevated in breast cancer cells and correlates with a significant decrease in DNA replication fidelity. We also demonstrate that UV treatment of breast cancer cells additionally increases pol expression with a peak occurring between 30 min and 2 h after cellular insult. This implies that the change in pol expression is an early event after UV-mediated DNA damage. That pol may play a role in the higher mutation frequencies observed in breast cancer cells was suggested when a reduction in mutation frequency was found after pol was immunodepleted from nuclear extracts of the cells. Analysis of the UV-induced mutation spectra revealed that >90% were point mutations. The analysis also demonstrated a decreased C3 T nucleotide transition and an increased C3 A transversion rate. Overall, our data strongly suggest that pol may be involved in the generation of both increased spontaneous and translesion mutations during DNA replication in breast cancer cells, thereby contributing to the accumulation of genetic damage.