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Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2, as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3−/−Rag1−/− and circKcnt2−/−Rag1−/− mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis., Type 3 innate lymphoid cells (ILC3) are involved in maintaining gut immune homeostasis. Here the authors identify a circular RNA, circKcnt2, to be induced in ILC3s from inflamed gut, yet circKcnt2 deletion aggravates mouse experimental colitis, thereby implicating circKcnt2 as a potential feedback regulator of ILC3 activation and gut immunity.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer., Metabolic adaptation has been reported to promote cancer, yet the underlying mechanisms are not clear. Here, the authors show that m1A methylation in tRNA regulates cholesterol metabolism in liver cancer stem cells and m1A inhibition decreases tumourigenesis in preclinical models of hepatocellular carcinoma.

Temporal and spatial-specific regulation of pluripotency networks is largely dependent on the precise modifications of core transcription factors. Misregulation of glutamylation is implicated in severe physiological abnormalities. However, how glutamylation regulates cell reprogramming and pluripotency networks remains elusive. Here we show that cytosolic carboxypeptidases 1 (CCP1) or CCP6 deficiency substantially promotes induced pluripotent cell (iPSC) induction and pluripotency of embryonic stem cells (ESCs). Klf4 polyglutamylation at Glu381 by tubulin tyrosine ligase-like 4 (TTLL4) and TTLL1 during cell reprogramming impedes its lysine 48-linked ubiquitination and sustains Klf4 stability. Klf4-E381A knockin mice display impaired blastocyst development and embryonic lethality. Deletion of TTLL4 or TTLL1 abrogates cell reprogramming and early embryogenesis. Thus, Klf4 polyglutamylation plays a critical role in the regulation of cell reprogramming and pluripotency maintenance., Embryonic stem cell pluripotency depends upon precise regulation by a core transcription network. Here the authors show that polyglutamylation mediated stabilization of the transcription factor Klf4 by TTLL1 and TTLL4 promotes reprogramming, pluripotency and preimplantation embryonic development.

Group 3 innate lymphoid cells (ILC3) promote lymphoid organogenesis and potentiate immune responses against bacterial infection. However, how ILC3 cells are developed and maintained is still unclear. Here, we show that carboxypeptidase CCP2 is highly expressed in common helper-like innate lymphoid progenitors, the progenitor of innate lymphoid cells, and CCP2 deficiency increases ILC3 numbers. Interleukin-7 receptor subunit alpha (IL-7Rα) is identified as a substrate of CCP2 for deglutamylation, and IL-7Rα polyglutamylation is catalyzed by polyglutamylases TTLL4 and TTLL13 in common helper-like innate lymphoid progenitors. IL-7Rα polyglutamylation triggers STAT5 activation to initiate transcription factor Sall3 expression in common helper-like innate lymphoid progenitors, which drives ILC3 cell differentiation. Moreover, Ttll4 −/− or Ttll13 −/− mice have reduced IL-7Rα polyglutamylation and Sall3 expression in common helper-like innate lymphoid progenitors. Importantly, mice with IL-7Rα E446A mutation have reduced Sall3 expression and ILC3 population. Thus, polyglutamylation and deglutamylation of IL-7Rα tightly controls the development and effector functions of ILC3s., Innate lymphoid cells (ILC) are important regulators of mucosal immunity, but how their development and homeostasis are modulated is still unclear. Here the authors show that the differentiation of group 3 ILCs is controlled by the glutamylation of IL-7Rα and the induction of transcription factor Sall3.

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC). However, the biology of hepatic CSCs remains largely undefined. Through analysis of transcriptome microarray data, we identify a long noncoding RNA (lncRNA) called lncBRM, which is highly expressed in liver CSCs and HCC tumours. LncBRM is required for the self-renewal maintenance of liver CSCs and tumour initiation. In liver CSCs, lncBRM associates with BRM to initiate the BRG1/BRM switch and the BRG1-embedded BAF complex triggers activation of YAP1 signalling. Moreover, expression levels of lncBRM together with YAP1 signalling targets are positively correlated with tumour severity of HCC patients. Therefore, lncBRM and YAP1 signalling may serve as biomarkers for diagnosis and potential drug targets for HCC., Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence of hepatocellular carcinoma. Here, the authors show that the long coding RNA, LcnBRM, regulates the self-renewal of liver CSCs and tumour initiation through binding to BAF complex thereby activating YAP1.

Damage-associated molecular patterns (DAMP) trigger innate immune response and exacerbate inflammation to combat infection and cellular damage. Identifying DAMPs and revealing their functions are thus of crucial importance. Here we report that two molecules, N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs and are released by activated macrophages during lipopolysaccharide-induced septic shock or acetaminophen-induced liver injury. We show that extracellular NMI and IFP35 activate macrophages to release proinflammatory cytokines by activating nuclear factor-κB through the Toll-like receptor 4 pathway. In addition, the serum levels of NMI are increased in patients who succumbed to severe inflammation. NMI deficiency reduces inflammatory responses and mortality in mouse models of sepsis and liver injury. We therefore propose that extracellular NMI and IFP35 exacerbate inflammation as DAMPs, making them potential therapeutic targets for clinical intervention., Damage-associated molecular patterns (DAMP) are important mediators of innate immunity. Here the authors show that N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs to promote inflammation by activating macrophages via the Toll-like receptor 4 and NF-κB pathways.