| 1. |
- Bécoulet, A., et al.
(författare)
-
Science and technology research and development in support to ITER and the Broader Approach at CEA
- 2013
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10
-
Tidskriftsartikel (refereegranskat)abstract
- In parallel to the direct contribution to the procurement phase of ITER and Broader Approach, CEA has initiated research & development programmes, accompanied by experiments together with a significant modelling effort, aimed at ensuring robust operation, plasma performance, as well as mitigating the risks of the procurement phase. This overview reports the latest progress in both fusion science and technology including many areas, namely the mitigation of superconducting magnet quenches, disruption-generated runaway electrons, edge-localized modes (ELMs), the development of imaging surveillance, and heating and current drive systems for steady-state operation. The WEST (W Environment for Steady-state Tokamaks) project, turning Tore Supra into an actively cooled W-divertor platform open to the ITER partners and industries, is presented.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Wang, Zhaoming, et al.
(författare)
-
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
|
|
| 6. |
- Machiela, Mitchell J., et al.
(författare)
-
Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
-
Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
|
|
| 7. |
- Machiela, Mitchell J, et al.
(författare)
-
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Jacobs, Kevin B, et al.
(författare)
-
Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
-
Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
-
Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
|
|
| 11. |
|
|
| 12. |
- McKay, James D., et al.
(författare)
-
Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
-
Tidskriftsartikel (refereegranskat)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
|
|
| 13. |
- Palmer, Elizabeth E., et al.
(författare)
-
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
-
Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
-
Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
|
|
| 14. |
- Pearce, Neil E, et al.
(författare)
-
IARC Monographs : 40 Years of Evaluating Carcinogenic Hazards to Humans
- 2015
-
Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 507-514
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also the approach used to perform these evaluations. Some critics have claimed that IARC Working Groups' failures to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.OBJECTIVES: The authors of this paper are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We have examined here criticisms of the IARC classification process to determine the validity of these concerns. We review the history of IARC evaluations and describe how the IARC evaluations are performed.DISCUSSION: We conclude that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various discipline and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Acciarri, R., et al.
(författare)
-
Demonstration of MeV-scale physics in liquid argon time projection chambers using ArgoNeuT
- 2019
-
Ingår i: Physical Review D. - : AMER PHYSICAL SOC. - 2470-0010 .- 2470-0029. ; 99:1
-
Tidskriftsartikel (refereegranskat)abstract
- MeV-scale energy depositions by low-energy photons produced in neutrino-argon interactions have been identified and reconstructed in ArgoNeuT liquid argon time projection chamber (LArTPC) data. ArgoNeuT data collected on the NuMI beam at Fermilab were analyzed to select isolated low-energy depositions in the TPC volume. The total number, reconstructed energies, and positions of these depositions have been compared to those from simulations of neutrino-argon interactions using the FLUKA Monte Carlo generator. Measured features are consistent with energy depositions from photons produced by deexcitation of the neutrino's target nucleus and by inelastic scattering of primary neutrons produced by neutrino-argon interactions. This study represents a successful reconstruction of physics at the MeV scale in a LArTPC, a capability of crucial importance for detection and reconstruction of supernova and solar neutrino interactions in future large LArTPCs.
|
|
| 18. |
- Hung, Rayjean J., et al.
(författare)
-
Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region
- 2019
-
Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 14:8, s. 1360-1369
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
|
|
| 19. |
- Byun, Jinyoung, et al.
(författare)
-
Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer
- 2022
-
Ingår i: Nature Genetics. - : Nature Research. - 1061-4036 .- 1546-1718. ; 54:8, s. 1167-1177
-
Tidskriftsartikel (refereegranskat)abstract
- To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.
|
|
| 20. |
- Ding, Li, et al.
(författare)
-
Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
-
Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
|
|
| 21. |
- Landälv, Ludvig, 1982-, et al.
(författare)
-
Structural evolution in reactive RF magnetron sputtered (Cr,Zr)2O3 coatings during annealing
- 2017
-
Ingår i: Acta Materialia. - : PERGAMON-ELSEVIER SCIENCE LTD. - 1359-6454 .- 1873-2453. ; 131, s. 543-552
-
Tidskriftsartikel (refereegranskat)abstract
- Reactive RF-magnetron sputtering is used to grow Cr0.28Zr0.10O0.61 coatings at 500 degrees C. Coatings are annealed at 750 degrees C, 810 degrees C, and 870 degrees C. The microstructure evolution of the pseudobinary oxide compound is characterized through high resolution state of the art HRSTEM and HREDX-maps, revealing the segregation of Cr and Zr on the nm scale. The as-deposited coating comprises cc-(Cr,Zr)(2)O-3 solid solution with a Zr-rich (Zr,Cr)O-x. amorphous phase. After annealing to 750 degrees C tetragonal ZrO2 nucleates and grows from the amorphous phase. The ZrO2 phase is stabilized in its tetragonal structure at these fairly low annealing temperatures, possibly due to the small grain size (below 30 nm). Correlated with the nucleation and growth of the tetragonal-ZrO2 phase is an increase in hardness, with a maximum hardness after annealing to 750 degrees C, followed by a decrease in hardness upon coarsening, bcc metallic Cr phase formation and loss of oxygen, during annealing to 870 degrees C. The observed phase segregation opens up future design routes for pseudobinary oxides with tunable microstructural and mechanical properties. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
|
|
| 22. |
- Ryvlin, Philippe, et al.
(författare)
-
Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS) : a retrospective study
- 2013
-
Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 12:10, s. 966-977
-
Tidskriftsartikel (refereegranskat)abstract
- Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. Methods Between Jan 1,2008, and Dec 29,2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. Findings 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5.1 (95% CI 2.6-9.2) per 1000 patient-years, with a risk of 1.2 (0.6-2.1) per 10 000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. Interpretation SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time.
|
|
| 23. |
- Beck, M., et al.
(författare)
-
Evaluation of the energetic position of the lowest excited singlet state of beta-carotene by NEXAFS and photoemission spectroscopy
- 2001
-
Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - 0005-2728 .- 1879-2650. ; 1506:3, s. 260-267
-
Tidskriftsartikel (refereegranskat)abstract
- In carotenoids the lowest energetic optical transition belonging to the pi -electron system is forbidden by symmetry, therefore the energetic position of the S-1 (2(1)A(g)) level can hardly be assessed by optical spectroscopy. We introduce a novel experimental approach: For molecules with ir-electron systems the transition C1s --> 2p(pi*) from inner-atomic to the lowest unoccupied molecular orbital (LUMO) appears in X-ray absorption near edge spectra (NEXAFS) as an intense, sharp peak a few eV below the carbon K-edge. Whereas the peak position reflects the energy of the First excited singlet state in relation to the ionization potential of the molecule, intensity and width of the transition depend on hybridization and bonding partners of the selected atom. Complementary information can be obtained from ultraviolet photoelectron spectroscopy (UPS): At the low binding energy site of the spectrum a peak related to the highest occupied molecular orbital (HOMO) appears. We have measured NEXAFS and UPS of beta -carotene. Based on these measurements and quantum chemical calculations the HOMO and LUMO energies can be derived.
|
|
| 24. |
|
|
| 25. |
- Rowe, Helen M., et al.
(författare)
-
KAP1 controls endogenous retroviruses in embryonic stem cells
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 463, s. 40-237
-
Tidskriftsartikel (refereegranskat)abstract
- More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs). Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity, remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex, but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesis, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells. Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5' untranslated region (5'UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5'UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development.
|
|
