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1.
bioRxiv ; 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-38076897

RESUMO

Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that while the fundamental properties of topologically associating domains (TADs) remain largely stable, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD-TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on chromosome 10. This insertion leads to the formation of de novo enhancer contacts and activation of the oncogene, illustrating how structural variants can interact with the 3D genome to drive oncogenic states. In summary, our findings provide evidence for the degradation of genome organization at multiple scales during breast cancer progression revealing novel relationships between genome 3D structure and oncogenic processes.

2.
EMBO J ; 36(19): 2829-2843, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28814448

RESUMO

The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer.


Assuntos
Carcinógenos/toxicidade , Transformação Celular Neoplásica , Resistência a Medicamentos/genética , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/genética , Mutagênese , Sequência de Bases/fisiologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Células Cultivadas , Dano ao DNA , Resistência a Medicamentos/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Melanoma/etiologia , Melanoma/genética , Mutagênese/efeitos dos fármacos , Mutagênese/genética , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Raios Ultravioleta , Melanoma Maligno Cutâneo
3.
Nucleic Acids Res ; 42(18): e143, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25114054

RESUMO

Identification of three-dimensional (3D) interactions between regulatory elements across the genome is crucial to unravel the complex regulatory machinery that orchestrates proliferation and differentiation of cells. ChIA-PET is a novel method to identify such interactions, where physical contacts between regions bound by a specific protein are quantified using next-generation sequencing. However, determining the significance of the observed interaction frequencies in such datasets is challenging, and few methods have been proposed. Despite the fact that regions that are close in linear genomic distance have a much higher tendency to interact by chance, no methods to date are capable of taking such dependency into account. Here, we propose a statistical model taking into account the genomic distance relationship, as well as the general propensity of anchors to be involved in contacts overall. Using both real and simulated data, we show that the previously proposed statistical test, based on Fisher's exact test, leads to invalid results when data are dependent on genomic distance. We also evaluate our method on previously validated cell-line specific and constitutive 3D interactions, and show that relevant interactions are significant, while avoiding over-estimating the significance of short nearby interactions.


Assuntos
Cromatina/química , Genômica/métodos , Modelos Estatísticos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA
4.
Stem Cells ; 32(10): 2780-93, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24898411

RESUMO

Differentiation of osteoblasts from mesenchymal stem cells (MSCs) is an integral part of bone development and homeostasis, and may when improperly regulated cause disease such as bone cancer or osteoporosis. Using unbiased high-throughput methods we here characterize the landscape of global changes in gene expression, histone modifications, and DNA methylation upon differentiation of human MSCs to the osteogenic lineage. Furthermore, we provide a first genome-wide characterization of DNA binding sites of the bone master regulatory transcription factor Runt-related transcription factor 2 (RUNX2) in human osteoblasts, revealing target genes associated with regulation of proliferation, migration, apoptosis, and with a significant overlap with p53 regulated genes. These findings expand on emerging evidence of a role for RUNX2 in cancer, including bone metastases, and the p53 regulatory network. We further demonstrate that RUNX2 binds to distant regulatory elements, promoters, and with high frequency to gene 3' ends. Finally, we identify TEAD2 and GTF2I as novel regulators of osteogenesis.


Assuntos
Diferenciação Celular/genética , Osteogênese/genética , Processamento Alternativo/genética , Sequência de Bases , Sítios de Ligação , Linhagem da Célula/genética , Cromatina/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Epigênese Genética , Genoma Humano/genética , Humanos , Células-Tronco Mesenquimais/citologia , Dados de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
Nucleic Acids Res ; 41(10): 5164-74, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23571755

RESUMO

The study of chromatin 3D structure has recently gained much focus owing to novel techniques for detecting genome-wide chromatin contacts using next-generation sequencing. A deeper understanding of the architecture of the DNA inside the nucleus is crucial for gaining insight into fundamental processes such as transcriptional regulation, genome dynamics and genome stability. Chromatin conformation capture-based methods, such as Hi-C and ChIA-PET, are now paving the way for routine genome-wide studies of chromatin 3D structure in a range of organisms and tissues. However, appropriate methods for analyzing such data are lacking. Here, we propose a hypothesis test and an enrichment score of 3D co-localization of genomic elements that handles intra- or interchromosomal interactions, both separately and jointly, and that adjusts for biases caused by structural dependencies in the 3D data. We show that maintaining structural properties during resampling is essential to obtain valid estimation of P-values. We apply the method on chromatin states and a set of mutated regions in leukemia cells, and find significant co-localization of these elements, with varying enrichment scores, supporting the role of chromatin 3D structure in shaping the landscape of somatic mutations in cancer.


Assuntos
Cromatina/química , Linhagem Celular Tumoral , Cromossomos Humanos/química , Interpretação Estatística de Dados , Genoma , Humanos , Leucemia/genética , Mutação , Conformação de Ácido Nucleico , Análise de Sequência de DNA
6.
J Sep Sci ; 28(3): 295-300, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15776934

RESUMO

This paper discusses the behaviour of five small model peptides in a three phase (aqueous donor-organic-aqueous acceptor) liquid phase micro extraction system in relation to their physico-chemical properties (charge, hydrophobicity). It is proved that for all peptides transport over the organic phase is mediated by aliphatic sulphonic acids. Heptane-1-sulphonic acid gave the best overall recoveries. It appeared that peptides with hydrophobic properties (IPI) and a high number of positive charges (KYK) show good recoveries and are enriched in the acceptor phase. Variation in the pH (1.6-4.4) of the donor phase shows that there are peptide-dependent optimal pH-values for their recovery. Increasing pH in the acceptor phase shows that in most cases the recovery decreases due to decreased ion-pair mediated membrane transport. For KYK the partition between the organic phase and the aqueous acceptor-phase is also driven by the solubility in the aqueous acceptor phase. Increase of the ion strength of the acceptor phase did not affect the recovery of the peptides. Except for KYK, which showed decreased recovery when the ion strength increased. Another finding is that delocalisation of positive charge causes bad recovery, probably due to incomplete ion-pair-peptide complex formation.


Assuntos
Ácidos/química , Peptídeos/química , Peptídeos/isolamento & purificação , Concentração de Íons de Hidrogênio , Íons/química , Modelos Químicos , Prótons
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