Analysis of histone modifications at human ribosomal DNA in liver cancer cell

Fang

et al. 2019

Preprint

BackgroundRecently, liquid biopsy for cancer detection has pursued great progress. However, there are still a lack of high quality markers. It is a challenge to detect cancer stably and accurately in plasma cell free DNA (cfDNA), when the ratio of cancer signal is low. Repetitive genes or elements may improve the robustness of signals. In this study, we focused on ribosomal DNA which repeats hundreds of times in human diploid genome and investigated performances for cancer detection in plasma. ResultsWe collected bisulfite sequencing samples including normal tissues and 4 cancer types and found that intergenic spacer (IGS) of rDNA has high methylation levels and low variation in normal tissues and plasma. Strikingly, IGS of rDNA shows significant hypo-methylation in tumors compared with normal tissues. Further, we collected plasma bisulfite sequencing data from 224 healthy subjects and cancer patients. Means of AUC in testing set were 0.96 (liver cancer), 0.94 (lung cancer and), 0.92 (colon cancer) with classifiers using only 10 CpG sites. Due to the feature of high copy number, when liver cancer plasma WGBS was down-sampled to 10 million raw reads (0.25× whole genome coverage), the prediction performance decreased only a bit (mean AUC=0.93). Finally, methylation of rDNA could also be used for monitor cancer progression and treatment. ConclusionTaken together, we provided the high-resolution map of rDNA methylation in tumors and supported that methylation of rDNA was a competitive and robust marker for detecting cancer and monitoring cancer progression in plasma.

Section: Aberrant Methylation Of Rdna In Malignant Tumorssupporting

confidence: 56%

mentioning

confidence: 99%

Ribosomal DNA methylation as stable biomarkers for detection of cancer in plasma

Fang

et al. 2019

Preprint

“…We suggest that enrichment of marks associated with active chromatin may be the result of these regions maintaining chromatin states that are important for rDNA function. Overall, given that the majority of IGS conserved regions fall into these zones and that the presence of active chromatin states has been documented in these regions previously [59,136], testing these zones for function is a high priority.…”

Section: Discussionmentioning

confidence: 99%

The conservation landscape of the human ribosomal RNA gene repeats

Agrawal

Ganley

2018

PLoS ONE

Ribosomal RNA gene repeats (rDNA) encode ribosomal RNA, a major component of ribosomes. Ribosome biogenesis is central to cellular metabolic regulation, and several diseases are associated with rDNA dysfunction, notably cancer, However, its highly repetitive nature has severely limited characterization of the elements responsible for rDNA function. Here we make use of phylogenetic footprinting to provide a comprehensive list of novel, potentially functional elements in the human rDNA. Complete rDNA sequences for six non-human primate species were constructed using de novo whole genome assemblies. These new sequences were used to determine the conservation profile of the human rDNA, revealing 49 conserved regions in the rDNA intergenic spacer (IGS). To provide insights into the potential roles of these conserved regions, the conservation profile was integrated with functional genomics datasets. We find two major zones that contain conserved elements characterised by enrichment of transcription-associated chromatin factors, and transcription. Conservation of some IGS transcripts in the apes underpins the potential functional significance of these transcripts and the elements controlling their expression. Our results characterize the conservation landscape of the human IGS and suggest that noncoding transcription and chromatin elements are conserved and important features of this unique genomic region.

“…and is associated with cell proliferation, tumour staging and the prognosis of tumour cells [ 8 – 10 ]. Some data suggest that HCC is associated with the following factors: cancer gene mutation, amplification, fusion; tumour suppressor gene loss of activity; genetic disequilibrium (DNA copy number variation); and abnormal regulation of DNA sequences (promoter methylation) [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

The role of kinesin KIF18A in the invasion and metastasis of hepatocellular carcinoma

Luo

Liao

et al. 2018

World J Surg Onc

BackgroundKIF18A is associated with a variety of tumours; however, the specific mechanism of action of KIF18A in hepatocellular carcinoma (HCC) remains unclear. In this study, in vitro and in vivo experiments were performed with the aim of exploring the potential function and molecular mechanism of kinesin KIF18A in the occurrence and development of HCC.MethodsWe detected the expression of KIF18A in tumour and adjacent tissues as well as cell proliferation, cell invasion and migration in hepatoma cells after silencing KIF18A. KIF18A-silenced hepatoma cells were subcutaneously injected into nude mice to verify the tumorigenicity of KIF18A. We also detected the expression of signal pathway-related proteins in hepatoma cells after KIF18A knockdown with the aim of exploring the association between KIF18A and related signalling pathways.ResultsThe level of KIF18A protein was higher in liver cancer tissues than adjacent tissues. After silencing KIF18A in SMMC-7721 and HepG2 cells, cell growth was obviously inhibited; the migration and invasion abilities were significantly decreased and the in vivo tumour weight was decreased compared to the control group (0.201 ± 0.088 g vs 0.476 ± 0.126 g, p = 0.009). The expression of cell cycle-related protein (cyclin B1), invasion and metastasis-related proteins (MMP-7 and MMP-9) and Akt-related proteins in hepatoma cells was also decreased after knocking down KIF18A.ConclusionsKIF18A may promote proliferation, invasion and metastasis of HCC cells by promoting the cell cycle signalling pathway as well as the Akt and MMP-7/MMP-9-related signalling pathways and may serve as a new target for the diagnosis and treatment of HCC.