Polycomb repressive complex 2 (PRC2) catalyzes histone methylation at H3 Lys27, and plays crucial roles during development and diseases in numerous systems. Its catalytic subunit EZH2 represents a key nuclear target for long non-coding RNAs (lncRNAs) that emerging to be a novel class of epigenetic regulator and participate in diverse cellular processes. LncRNAs are characterized by high tissue-specificity; however, little is known about the tissue profile of the EZH2-interacting lncRNAs. Here we performed a global screening for EZH2-binding lncRNAs in tissues including brain, lung, heart, liver, kidney, intestine, spleen, testis, muscle and blood by combining RNA immuno- precipitation and RNA sequencing. We identified 1328 EZH2-binding lncRNAs, among which 470 were shared in at least two tissues while 858 were only detected in single tissue. An RNA motif with specific secondary structure was identified in a number of lncRNAs, albeit not in all EZH2-binding lncRNAs. The EZH2-binding lncRNAs fell into four categories including intergenic lncRNA, antisense lncRNA, intron-related lncRNA and promoter-related lncRNA, suggesting diverse regulations of both cis and trans-mechanisms. A promoter-related lncRNA Hnf1aos1 bound to EZH2 specifically in the liver, a feature same as its paired coding gene Hnf1a, further confirming the validity of our study. In addition to the well known EZH2-binding lncRNAs like Kcnq1ot1, Gas5, Meg3, Hotair and Malat1, majority of the lncRNAs were firstly reported to be associated with EZH2. Our findings provide a profiling view of the EZH2-interacting lncRNAs across different tissues, and suggest critical roles of lncRNAs during cell differentiation and maturation.

Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding–induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8 -knockout or Mfge8 -overexpressing mice, the activated Akt/PKB (protein kinase B)–Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II–treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy.

Background: Tai Chi exercise has been reported to enhance physical and mental health in the older adults; however, the mechanism remains elusive. Trial design: We recruited 289 older adults practicing Tai Chi for over 3 years, together with 277 age-matched older and 102 young adults as controls. 168 Tai Chi practitioners were successfully matched to 168 older controls aged 60–69 based on a propensity score for statistics. Methods: Cerebrovascular function was evaluated by measuring the hemodynamics of the carotid artery. Spearman correlation was performed to validate the age-associated physiological parameters. Results: Cerebrovascular function in older adults significantly degenerated compared with the young, and was substantially correlated with age. Compared with the older control group, Tai Chi practitioners showed significant improvements in CVHI (cerebral vascular hemodynamics indices) Score (P = 0.002), mean blood flow velocity (P = 0.014), maximal blood flow velocity (P = 0.04) and minimum blood flow velocity (P < 0.001), whereas the age-related increases in pulse wave velocity (P = 0.022), characteristic impedance (P = 0.021) and peripheral resistance (P = 0.044) were lowered. Conclusions: These data demonstrate a rejuvenation role of Tai Chi in improving the age-related decline of the cerebrovascular function. Trial registration: Chinese Clinical Trial Registry (ChiCTR1900025187)

Signal transducer and activator of transcription 3 (STAT3) is essential for cell signaling in response to extracellular stimuli, and its overactivation is a hallmark of inflammation and tumorigenesis. The differential mechanisms underlying the physiological and pathological regulation of STAT3 remain elusive. Here, we demonstrated that cryptic splice sites in STAT3 generated heterogeneous isoforms with or without a single amino acid Ser701 (wS701/ΔS701), with the latter being more abundant in colon cancers. Intrinsic S701 underwent reversible phosphorylation catalyzed by mechanistic target of rapamycin complex 1 (mTORC1) and protein phosphatase 2A (PP2A). Upon inflammatory stimulation, phosphorylation at S701 (p-S701) sequestered Y705 phosphorylation (p-Y705) by interfering with the access of Janus kinase 1/2 and restricting STAT3 overactivation. In contrast, the STAT3_ΔS701 isoform was hyperactive because of the absence of this self-restricting mechanism. Deletion of S701 in mice increased susceptibility to colonic inflammation and tumorigenesis. Pharmacological inhibition of PP2A sustained p-S701 and alleviated colon inflammation in wild-type but not in ΔS701 mice. Our findings highlight the importance of STAT3 heterogeneity in colonic inflammation and colorectal cancer.