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Author Report for: Le N

Title: Differential expression and hypoxia-mediated regulation of the N-myc downstream regulated gene family
Le N, Hufford TM, Park JS, Brewster RM
Ref: FASEB Journal, 35:e21961, 2021 : PubMed
Abstract


ESTHER: Le_2021_FASEB.J_35_e21961
PubMedSearch: Le 2021 FASEB.J 35 e21961
PubMedID: 34665878

Abstract

Many organisms rely on oxygen to generate cellular energy (adenosine triphosphate or ATP). During severe hypoxia, the production of ATP decreases, leading to cell damage or death. Conversely, excessive oxygen causes oxidative stress that is equally damaging to cells. To mitigate pathological outcomes, organisms have evolved mechanisms to adapt to fluctuations in oxygen levels. Zebrafish embryos are remarkably hypoxia-tolerant, surviving anoxia (zero oxygen) for hours in a hypometabolic, energy-conserving state. To begin to unravel underlying mechanisms, we analyze here the distribution of the N-myc Downstream Regulated Gene (ndrg) family, ndrg1-4, and their transcriptional response to hypoxia. These genes have been primarily studied in cancer cells and hence little is understood about their normal function and regulation. We show here using in situ hybridization that ndrgs are expressed in metabolically demanding organs of the zebrafish embryo, such as the brain, kidney, and heart. To investigate whether ndrgs are hypoxia-responsive, we exposed embryos to different durations and severity of hypoxia and analyzed transcript levels. We observed that ndrgs are differentially regulated by hypoxia and that ndrg1a has the most robust response, with a ninefold increase following prolonged anoxia. We further show that this treatment resulted in de novo expression of ndrg1a in tissues where the transcript is not observed under normoxic conditions and changes in Ndrg1a protein expression post-reoxygenation. These findings provide an entry point into understanding the role of this conserved gene family in the adaptation of normal cells to hypoxia and reoxygenation.



        

Title: The receptor protein tyrosine phosphatase CLR-1 is required for synaptic partner recognition
Varshney A, Benedetti K, Watters K, Shankar R, Tatarakis D, Coto Villa D, Magallanes K, Agenor V, Wung W and VanHoven M <7 more author(s)> Varshney A, Benedetti K, Watters K, Shankar R, Tatarakis D, Coto Villa D, Magallanes K, Agenor V, Wung W, Farah F, Ali N, Le N, Pyle J, Farooqi A, Kieu Z, Bremer M, VanHoven M (- 7)
Ref: PLoS Genet, 14:e1007312, 2018 : PubMed
Abstract


ESTHER: Varshney_2018_PLoS.Genet_14_e1007312
PubMedSearch: Varshney 2018 PLoS.Genet 14 e1007312
PubMedID: 29742100

Abstract

During neural circuit formation, most axons are guided to complex environments, coming into contact with multiple potential synaptic partners. However, it is critical that they recognize specific neurons with which to form synapses. Here, we utilize the split GFP-based marker Neuroligin-1 GFP Reconstitution Across Synaptic Partners (NLG-1 GRASP) to visualize specific synapses in live animals, and a circuit-specific behavioral assay to probe circuit function. We demonstrate that the receptor protein tyrosine phosphatase (RPTP) clr-1 is necessary for synaptic partner recognition (SPR) between the PHB sensory neurons and the AVA interneurons in C. elegans. Mutations in clr-1/RPTP result in reduced NLG-1 GRASP fluorescence and impaired behavioral output of the PHB circuit. Temperature-shift experiments demonstrate that clr-1/RPTP acts early in development, consistent with a role in SPR. Expression and cell-specific rescue experiments indicate that clr-1/RPTP functions in postsynaptic AVA neurons, and overexpression of clr-1/RPTP in AVA neurons is sufficient to direct additional PHB-AVA synaptogenesis. Genetic analysis reveals that clr-1/RPTP acts in the same pathway as the unc-6/Netrin ligand and the unc-40/DCC receptor, which act in AVA and PHB neurons, respectively. This study defines a new mechanism by which SPR is governed, and demonstrates that these three conserved families of molecules, with roles in neurological disorders and cancer, can act together to regulate communication between cells.



        

Title: Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
Lawrenson K, Kar S, McCue K, Kuchenbaeker K, Michailidou K, Tyrer J, Beesley J, Ramus SJ, Li Q and Gayther SA <272 more author(s)> Lawrenson K, Kar S, McCue K, Kuchenbaeker K, Michailidou K, Tyrer J, Beesley J, Ramus SJ, Li Q, Delgado MK, Lee JM, Aittomaki K, Andrulis IL, Anton-Culver H, Arndt V, Arun BK, Arver B, Bandera EV, Barile M, Barkardottir RB, Barrowdale D, Beckmann MW, Benitez J, Berchuck A, Bisogna M, Bjorge L, Blomqvist C, Blot W, Bogdanova N, Bojesen A, Bojesen SE, Bolla MK, Bonanni B, Borresen-Dale AL, Brauch H, Brennan P, Brenner H, Bruinsma F, Brunet J, Buhari SA, Burwinkel B, Butzow R, Buys SS, Cai Q, Caldes T, Campbell I, Canniotto R, Chang-Claude J, Chiquette J, Choi JY, Claes KB, Cook LS, Cox A, Cramer DW, Cross SS, Cybulski C, Czene K, Daly MB, Damiola F, Dansonka-Mieszkowska A, Darabi H, Dennis J, Devilee P, Diez O, Doherty JA, Domchek SM, Dorfling CM, Dork T, Dumont M, Ehrencrona H, Ejlertsen B, Ellis S, Engel C, Lee E, Evans DG, Fasching PA, Feliubadalo L, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foretova L, Fostira F, Foulkes WD, Fridley BL, Friedman E, Frost D, Gambino G, Ganz PA, Garber J, Garcia-Closas M, Gentry-Maharaj A, Ghoussaini M, Giles GG, Glasspool R, Godwin AK, Goldberg MS, Goldgar DE, Gonzalez-Neira A, Goode EL, Goodman MT, Greene MH, Gronwald J, Guenel P, Haiman CA, Hall P, Hallberg E, Hamann U, Hansen TV, Harrington PA, Hartman M, Hassan N, Healey S, Heitz F, Herzog J, Hogdall E, Hogdall CK, Hogervorst FB, Hollestelle A, Hopper JL, Hulick PJ, Huzarski T, Imyanitov EN, Isaacs C, Ito H, Jakubowska A, Janavicius R, Jensen A, John EM, Johnson N, Kabisch M, Kang D, Kapuscinski M, Karlan BY, Khan S, Kiemeney LA, Kjaer SK, Knight JA, Konstantopoulou I, Kosma VM, Kristensen V, Kupryjanczyk J, Kwong A, de la Hoya M, Laitman Y, Lambrechts D, Le N, De Leeneer K, Lester J, Levine DA, Li J, Lindblom A, Long J, Lophatananon A, Loud JT, Lu K, Lubinski J, Mannermaa A, Manoukian S, Le Marchand L, Margolin S, Marme F, Massuger LF, Matsuo K, Mazoyer S, McGuffog L, McLean C, McNeish I, Meindl A, Menon U, Mensenkamp AR, Milne RL, Montagna M, Moysich KB, Muir K, Mulligan AM, Nathanson KL, Ness RB, Neuhausen SL, Nevanlinna H, Nord S, Nussbaum RL, Odunsi K, Offit K, Olah E, Olopade OI, Olson JE, Olswold C, O'Malley D, Orlow I, Orr N, Osorio A, Park SK, Pearce CL, Pejovic T, Peterlongo P, Pfeiler G, Phelan CM, Poole EM, Pylkas K, Radice P, Rantala J, Rashid MU, Rennert G, Rhenius V, Rhiem K, Risch HA, Rodriguez G, Rossing MA, Rudolph A, Salvesen HB, Sangrajrang S, Sawyer EJ, Schildkraut JM, Schmidt MK, Schmutzler RK, Sellers TA, Seynaeve C, Shah M, Shen CY, Shu XO, Sieh W, Singer CF, Sinilnikova OM, Slager S, Song H, Soucy P, Southey MC, Stenmark-Askmalm M, Stoppa-Lyonnet D, Sutter C, Swerdlow A, Tchatchou S, Teixeira MR, Teo SH, Terry KL, Terry MB, Thomassen M, Tibiletti MG, Tihomirova L, Tognazzo S, Toland AE, Tomlinson I, Torres D, Truong T, Tseng CC, Tung N, Tworoger SS, Vachon C, van den Ouweland AM, van Doorn HC, van Rensburg EJ, Van't Veer LJ, Vanderstichele A, Vergote I, Vijai J, Wang Q, Wang-Gohrke S, Weitzel JN, Wentzensen N, Whittemore AS, Wildiers H, Winqvist R, Wu AH, Yannoukakos D, Yoon SY, Yu JC, Zheng W, Zheng Y, Khanna KK, Simard J, Monteiro AN, French JD, Couch FJ, Freedman ML, Easton DF, Dunning AM, Pharoah PD, Edwards SL, Chenevix-Trench G, Antoniou AC, Gayther SA (- 272)
Ref: Nat Commun, 7:12675, 2016 : PubMed
Abstract


ESTHER: Lawrenson_2016_Nat.Commun_7_12675
PubMedSearch: Lawrenson 2016 Nat.Commun 7 12675
PubMedID: 27601076

Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 x 10(-20)), ER-negative BC (P=1.1 x 10(-13)), BRCA1-associated BC (P=7.7 x 10(-16)) and triple negative BC (P-diff=2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 x 10(-3)) and ABHD8 (P<2 x 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.



        

Title: A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks
Kapoor M, Wang JC, Wetherill L, Le N, Bertelsen S, Hinrichs AL, Budde J, Agrawal A, Bucholz K and Goate A <13 more author(s)> Kapoor M, Wang JC, Wetherill L, Le N, Bertelsen S, Hinrichs AL, Budde J, Agrawal A, Bucholz K, Dick D, Harari O, Hesselbrock V, Kramer J, Nurnberger JI, Jr., Rice J, Saccone NL, Schuckit M, Tischfield J, Porjesz B, Edenberg HJ, Bierut L, Foroud T, Goate A (- 13)
Ref: Hum Genet, 132:1141, 2013 : PubMed
Abstract


ESTHER: Kapoor_2013_Hum.Genet_132_1141
PubMedSearch: Kapoor 2013 Hum.Genet 132 1141
PubMedID: 23743675

Abstract

Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 x 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 x 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 x 10(-7)) and PLCL1 genes (p = 4.1 x 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p </= 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 x 10(-3), 3 x 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.