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1.
Bioinformatics ; 38(11): 3109-3112, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35482479

RESUMO

SUMMARY: Methylartist is a consolidated suite of tools for processing, visualizing and analysing nanopore-derived modified base calls. All detectable methylation types (e.g. 5mCpG, 5hmC, 6mA) are supported, enabling integrated study of base pairs when modified naturally or as part of an experimental protocol. AVAILABILITY AND IMPLEMENTATION: Methylartist is implemented in Python and is installable via PyPI and bioconda. Source code and test data are available at https://github.com/adamewing/methylartist. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Nanoporos , Software
2.
Genome Res ; 28(5): 639-653, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29643204

RESUMO

The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)-/- mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including TF subfamily elements, and one GF subfamily example. One of the TF insertions carried a 3' transduction, allowing us to identify its donor L1 and to demonstrate that this full-length TF element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Retroelementos/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Transformação Celular Neoplásica/genética , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Mamíferos/genética , Camundongos Knockout , Pessoa de Meia-Idade , Mutagênese Insercional , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
3.
Mob DNA ; 7: 21, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27843499

RESUMO

BACKGROUND: LINE-1 (L1) retrotransposons are a notable endogenous source of mutagenesis in mammals. Notably, cancer cells can support unusual L1 retrotransposition and L1-associated sequence rearrangement mechanisms following DNA damage. Recent reports suggest that L1 is mobile in epithelial tumours and neural cells but, paradoxically, not in brain cancers. RESULTS: Here, using retrotransposon capture sequencing (RC-seq), we surveyed L1 mutations in 14 tumours classified as glioblastoma multiforme (GBM) or as a lower grade glioma. In four GBM tumours, we characterised one probable endonuclease-independent L1 insertion, two L1-associated rearrangements and one likely Alu-Alu recombination event adjacent to an L1. These mutations included PCR validated intronic events in MeCP2 and EGFR. Despite sequencing L1 integration sites at up to 250× depth by RC-seq, we found no tumour-specific, endonuclease-dependent L1 insertions. Whole genome sequencing analysis of the tumours carrying the MeCP2 and EGFR L1 mutations also revealed no endonuclease-dependent L1 insertions. In a complementary in vitro assay, wild-type and endonuclease mutant L1 reporter constructs each mobilised very inefficiently in four cultured GBM cell lines. CONCLUSIONS: These experiments altogether highlight the consistent absence of canonical L1 retrotransposition in GBM tumours and cultured cell lines, as well as atypical L1-associated sequence rearrangements following DNA damage in vivo.

4.
Biosci Rep ; 36(1): e00291, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26704887

RESUMO

The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential effector of necroptotic cell death. Two distinct human MLKL isoforms have previously been reported, but their capacities to trigger cell death have not been compared directly. Herein, we examine these two MLKL isoforms, and further probe the features of the human MLKL N-terminal domain that are required for cell death. Expression in HEK293T cells of the N-terminal 201 amino acids (aa) of human MLKL is sufficient to cause cell death, whereas expression of the first 154 aa is not. Given that aa 1-125 are able to initiate necroptosis, our findings indicate that the helix that follows this region restrains necroptotic activity, which is again restored in longer constructs. Furthermore, MLKL isoform 2 (MLKL2), which lacks much of the regulatory pseudokinase domain, is a much more potent inducer of cell death than MLKL isoform 1 (MLKL1) in ectopic expression studies in HEK293T cells. Modelling predicts that a C-terminal helix constrains the activity of MLKL1, but not MLKL2. Although both isoforms are expressed by human monocyte-derived macrophages at the mRNA level, MLKL2 is expressed at much lower levels. We propose that it may have a regulatory role in controlling macrophage survival, either in the steady state or in response to specific stimuli.


Assuntos
Regulação Enzimológica da Expressão Gênica , Macrófagos/enzimologia , Proteínas Quinases/biossíntese , Sobrevivência Celular , Células HEK293 , Humanos , Isoenzimas/biossíntese , Isoenzimas/química , Isoenzimas/genética , Macrófagos/patologia , Modelos Moleculares , Necrose , Proteínas Quinases/química , Proteínas Quinases/genética , Estrutura Terciária de Proteína
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