Interindividual variation in DNA methylation at a putative POMC metastable epiallele Is associated with obesity

The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named “metastable epialleles” could in principle explain this “missing heritability.” We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI. Using cohorts from different ethnic backgrounds, including a Gambian cohort, we found evidence suggesting that methylation of the POMC VMR is established in the early embryo and that offspring methylation correlates with the paternal somatic methylation pattern. Furthermore, it is associated with levels of maternal one-carbon metabolites at conception and stable during postnatal life. Together, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation

The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies2. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology3. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a a 'pill' that awakens the innate immune system to kill cancer metastases. © 2014 Macmillan Publishers Limited.Fil: Paolino, Magdalena. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Choidas, Axel. Lead Discovery Center GmbH; AlemaniaFil: Wallner, Stephanie. Medizinische Universitat Innsbruck; AustriaFil: Pranjic, Blanka. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Uribesalgo, Iris. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Loeser, Stefanie. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Jamieson, Amanda M.. University Brown; Estados UnidosFil: Langdon, Wallace Y.. University of Western Australia; AustraliaFil: Ikeda, Fumiyo. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Fededa, Juan Pablo. Institute Of Molecular Biotechnology, Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Cronin, Shane J.. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Nitsch, Roberto. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Schultz-Fademrecht, Carsten. Lead Discovery Center GmbH; AlemaniaFil: Eickhoff, Jan. Lead Discovery Center GmbH; AlemaniaFil: Menninger, Sascha. Lead Discovery Center GmbH; AlemaniaFil: Unger, Anke. Lead Discovery Center GmbH; AlemaniaFil: Torka, Robert. Institute for Biochemistry Max-Planck; AlemaniaFil: Gruber, Thomas. Medizinische Universitat Innsbruck; AustriaFil: Hinterleitner, Reinhard. Medizinische Universitat Innsbruck; AustriaFil: Baier, Gottfried. Medizinische Universitat Innsbruck; AustriaFil: Wolf, Dominik. University Hospital Bonn; Alemania. Medical University Innsbruck; AustriaFil: Ullrich, Axel. Institute for Biochemistry Max-Planck; AlemaniaFil: Klebl, Bert M.. Lead Discovery Center GmbH; AlemaniaFil: Penninger, Josef M.. Institute Of Molecular Biotechnology, Vienna; Austri