TY  - JOUR
A1  - Scognamiglio, Roberta
A1  - Cabezas-Wallscheid, Nina
A1  - Thier, Marc Christian
A1  - Altamura, Sandro
A1  - Reyes, Alejandro
A1  - Prendergast, Áine M.
A1  - Baumgärtner, Daniel
A1  - Carnevalli, Larissa S.
A1  - Atzberger, Ann
A1  - Haas, Simon
A1  - von Paleske, Lisa
A1  - Boroviak, Thorsten
A1  - Wörsdörfer, Philipp
A1  - Essers, Marieke A. G.
A1  - Kloz, Ulrich
A1  - Eisenman, Robert N.
A1  - Edenhofer, Frank
A1  - Bertone, Paul
A1  - Huber, Wolfgang
A1  - van der Hoeven, Franciscus
A1  - Smith, Austin
A1  - Trumpp, Andreas
T1  - Myc depletion induces a pluripotent dormant state mimicking diapause
JF  - Cell
N2  - Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.
KW  - hematopoietic stem cells
KW  - leukemia inhibitory factor
KW  - c-Myc
KW  - N-Myc
KW  - gene expression
KW  - embryonic stem cells
KW  - self-renewal
KW  - protein synthesis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190868
VL  - 164
IS  - 4
ER  - 
TY  - JOUR
A1  - Robertson, Kevin A.
A1  - Hsieh, Wei Yuan
A1  - Forster, Thorsten
A1  - Blanc, Mathieu
A1  - Lu, Hongjin
A1  - Crick, Peter J.
A1  - Yutuc, Eylan
A1  - Watterson, Steven
A1  - Martin, Kimberly
A1  - Griffiths, Samantha J.
A1  - Enright, Anton J.
A1  - Yamamoto, Mami
A1  - Pradeepa, Madapura M.
A1  - Lennox, Kimberly A.
A1  - Behlke, Mark A.
A1  - Talbot, Simon
A1  - Haas, Jürgen
A1  - Dölken, Lars
A1  - Griffiths, William J.
A1  - Wang, Yuqin
A1  - Angulo, Ana
A1  - Ghazal, Peter
T1  - An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway
JF  - PLoS Biology
N2  - In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.
KW  - microRNA
KW  - sterol pathway
KW  - multihit targeting
KW  - interferon signaling
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166666
VL  - 14
IS  - 3
ER  -