Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.

The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 × 10-6). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.This research has been conducted using the UK Biobank Resource under Application Number 9905. This work was supported by the UK Medical Research Council (Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2). Research in the S. Jackson laboratory is funded by Cancer Research UK (CRUK; programme grant C6/A18796), with Institute core funding provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S. Jackson receives salary from the University of Cambridge, supplemented by CRUK

Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes

BACKGROUND: Despite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, although it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals. The involvement of imprinted genes has also attracted much attention, not least because two of the earliest discovered were shown to be oppositely imprinted and antagonistic in their regulation of growth. The Igf2 gene encodes a paternally expressed ligand that promotes growth, while maternally expressed Igf2r encodes a cell surface receptor that restricts growth by sequestering Igf2 and targeting it for lysosomal degradation. There are now over 150 imprinted genes known in mammals, but no other clear examples of antagonistic gene pairs have been identified. The delta-like 1 gene (Dlk1) encodes a putative ligand that promotes fetal growth and in adults restricts adipose deposition. Conversely, Grb10 encodes an intracellular signalling adaptor protein that, when expressed from the maternal allele, acts to restrict fetal growth and is permissive for adipose deposition in adulthood. RESULTS: Here, using knockout mice, we present genetic and physiological evidence that these two factors exert their opposite effects on growth and physiology through a common signalling pathway. The major effects are on body size (particularly growth during early life), lean:adipose proportions, glucose regulated metabolism and lipid storage in the liver. A biochemical pathway linking the two cell signalling factors remains to be defined. CONCLUSIONS: We propose that Dlk1 and Grb10 define a mammalian growth axis that is separate from the IGF pathway, yet also features an antagonistic imprinted gene pair. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-014-0099-8) contains supplementary material, which is available to authorized users

DLK1 and the Notch pathway in the liver

Het is onduidelijk waarom bij sommige kinderen een kwaadaardige vorm van leverkanker ontstaat. Farah Falix onderzocht de rol van twee eiwitten, DLK1 en Notch2, tijdens de leverontwikkeling. Het DLK1-eiwit is normaal alleen aanwezig in de embryonale lever. Het verschijnt ook bij een hepatoblastoom (kwaadaardige leverkanker bij kinderen) maar lijkt geen rol te spelen bij het ontstaan daarvan. Transgene muizen met verhoogd DLK1-eiwit in de lever ontwikkelden namelijk geen levertumoren. Dit eiwit kan wel worden gebruikt om de ziekte vast te stellen. Falix toonde verder aan dat het Notch2-eiwit, dat ook belangrijk is in de embryonale fase, evenmin een rol speelt bij het ontstaan van een hepatoblastoom. Het blijkt wel onmisbaar te zijn voor de aanleg van de galwegen

Possible roles of DLK1 in the Notch pathway during development and disease

AbstractThe Delta-Notch pathway is an evolutionarily conserved signaling pathway which controls a broad range of developmental processes including cell fate determination, terminal differentiation and proliferation. In mammals, four Notch receptors (NOTCH1–4) and five activating canonical ligands (JAGGED1, JAGGED2, DLL1, DLL3 and DLL4) have been described. The precise function of noncanonical Notch ligands remains unclear. Delta-like 1 homolog (DLK1), the best studied noncanonical Notch ligand, has been shown to act as an inhibitor of Notch signaling in vitro, but its function in vivo is poorly understood. In this review we summarize Notch signaling during development and highlight recent studies in DLK1expression that reveal new insights into its function

DLK1, a serum marker for hepatoblastoma in young infants.

Hepatoblastoma is a malignant pediatric liver tumor. The currently used diagnostic serum marker for hepatoblastoma, a-fetoprotein (AFP), is not always reliable in infants with hepatoblastoma, due to the physiologically elevated levels of AFP in this age group. In this report, we show that Delta-like 1 homolog (DLK1), a protein highly expressed during fetal development, but almost completely absent after birth, and an established liver-stem cell marker, is a new candidate serum marker of hepatoblastoma, especially in young infants. Pediatr Blood Cancer 2012;59:743745. (c) 2011 Wiley Periodicals, Inc

Characterization of superfine down powder

Superfine down powder was produced from down fiber after it was cut into short pieces and ground on a purpose-built machine. Scanning electron microscopy photographs showed that the down fiber was ground into particles with some fiber fragments and a large amount of rod-shaped ultrafine powder. Particle size distribution analysis indicated that the average size of the down powder was 1.546lm. Fourier transform infrared analysis showed that the absorbing peaks around 1640, 1520, and 1230 cm-1 were sharper than those of the down fiber. X-ray diffraction analysis revealed that the crystallinity of the superfine down powder was a little lower than that of the down fiber. Thermogravimetric analysis showed that the thermal stability decreased when the down fiber was ground into powder. Differential scanning calorimetry analysis showed that the intensity of the heat absorbing peaks of the down powder was lower than that of the down fiber, so the down powder decomposed more readily than the down fiber

DLK1, a serum marker for hepatoblastoma in young infants

Hepatoblastoma is a malignant pediatric liver tumor. The currently used diagnostic serum marker for hepatoblastoma, a-fetoprotein (AFP), is not always reliable in infants with hepatoblastoma, due to the physiologically elevated levels of AFP in this age group. In this report, we show that Delta-like 1 homolog (DLK1), a protein highly expressed during fetal development, but almost completely absent after birth, and an established liver-stem cell marker, is a new candidate serum marker of hepatoblastoma, especially in young infants. Pediatr Blood Cancer 2012;59:743745. (c) 2011 Wiley Periodicals, In