| 341. |
- Dewhurst, Matthew R, et al.
(författare)
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Loss of hepatocyte cell division leads to liver inflammation and fibrosis
- 2020
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:11, s. 1009084-1009084
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Tidskriftsartikel (refereegranskat)abstract
- The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.
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| 342. |
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| 343. |
- Drögemüller, Cord, et al.
(författare)
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A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta
- 2009
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:7, s. e1000579-
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Tidskriftsartikel (refereegranskat)abstract
- Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene.
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| 344. |
- El Shahawy, Maha, et al.
(författare)
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Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid
- 2017
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Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity.
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| 345. |
- Elliott, Kerryn, et al.
(författare)
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Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers.
- 2018
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.
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| 346. |
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| 347. |
- Engstrom, PG, et al.
(författare)
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Complex Loci in human and mouse genomes
- 2006
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 2:4, s. 564-577
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Tidskriftsartikel (refereegranskat)
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| 348. |
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| 349. |
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| 350. |
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