Česká Genetická Banka

NATURE: 24. - 30. 8. 2012

Immunology: Licensed in the lungs

"In multiple sclerosis, the body's own immune cells attack the brain and spinal cord. But how they get there from peripheral tissues has been a mystery. Surprisingly, the lungs might be a key transit point."

http://www.nature.com/nature/journal/v488/n7413/full/488595a.html

Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2

"Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM)1. iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs)2. Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts5, 6, 7, our data, and also studies of Tet2-mutant human tumour cells8, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming."

http://www.nature.com/nature/journal/v488/n7413/full/nature11333.html

Is irisin a human exercise gene?

"Boström et al. report that exercise training induces the expression of the FNDC5 gene in human muscle, producing irisin, which can convert white fat into brown fat, so enhancing metabolic uncoupling and hence caloric expenditure, and propose that this is a new health promoting hormone1. This assertion is based on experimental evidence that exogenous FNDC5 induces uncoupling protein 1 (UCP1) expression in white subcutaneous adipocytes; overexpression of FNDC5 in liver (elevating systemic irisin) prevents diet-induced weight gain and metabolic dysfunction and stimulates oxygen consumption in mice; and FNDC5 mRNA expression levels double after exercise training in eight human skeletal muscle samples. However, the UCP1 induction was lower than observed during Brite2 formation or the level associated with an improved diabetes profile in humans3. Here we demonstrate that muscle FNDC5 induction occurs only in a minority of subjects—whereas all types of exercise training programmes4, 5, 6, 7, in the vast majority of people, yield some gain in cardiovascular or metabolic health, in our analysis of ~200 subjects muscle FNDC5 was increased only in highly active elderly subjects, whereas FNDC5 expression was unrelated to metabolic status, which casts doubt over the general relevance of skeletal muscle FNDC5 to human health."

http://www.nature.com/nature/journal/v488/n7413/full/nature11364.html

Recurrent R-spondin fusions in colon cancer

"Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics1. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer."

http://www.nature.com/nature/journal/v488/n7413/full/nature11282.html