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Many previous large-scale genome-wide association studies (GWAS) have found 269 risk areas closely related to the risk of prostate cancer in the human genome, which contain a large number of single nucleotide polymorphism (SNP) sites, but among them About 98% of SNP sites are located in non-coding regions of the genome.
Whether these non-coding regions are only statistically associated with prostate cancer, or play a biological role, how to affect the occurrence and development of prostate cancer, there is little known in previous studies, and the mechanism is also unclear.
An in-depth understanding of the relationship between these SNP sites and the progression of prostate cancer is not only conducive to a deeper understanding of the role of SNP sites, but also a key step in transforming SNP sites from discovery to clinical application.
On March 19, Professor Ren Shancheng from Shanghai Changhai Hospital, Professor Wei Gonghong from Fudan University School of Basic Medicine and Affiliated Tumor Hospital (formerly at the University of Oulu, Finland), and Professor He Housheng from the University of Toronto in Canada teamed up in Nature Communications An article published in the journal CRISPRi screens reveals a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.
The team’s previous series of studies have determined that most of the prostate cancer-related risk SNPs are enriched in non-coding cis-forms on the genome.
Regulatory elements (risk-associated cis-regulatory elements, rCREs) region.In this paper, we have studied the functions of 260 rCRE regions in prostate cancer cell lines through CRISPRi screening, and found that different rCRE has different effects in different cell lines, and these different effects may be due to the expression on the genome.
The influence of genetic modification.
The author further conducted an in-depth study on the rCRE containing rs11986220 in the 8q24.
21 risk area of prostate cancer.
This region is adjacent to the oncogenes MYC and PVT1 in prostate cancer.
However, previous studies have not found an association between the SNP genotype and MYC expression in the 8q24.
21 risk area.
The researchers found that there are two CTCF transcription binding sites in the 10.
4kb (-10kb) and 2.
2kb (-2kb) regions upstream of the MYC gene promoter.
Previous reports have shown that CTCF has an important regulatory effect on the high-level structure of chromatin.
In prostate cancer, methylation in the 10kb upstream region of MYC promotes MYC expression, while methylation in the 2kb region inhibits MYC expression.
It is precisely because of the changes in the genomic methylation of the -10kb region of MYC in V16A cells and 22RV1 cells that affect the transcriptional binding of CTCF, which affects the remote regulation of MYC expression by the rs11986220 site, making the same SNP site There are different effects in different cells.
The authors found that the level of methylation in this region also regulates the expression of PVT1.
The author further verified this result in clinical samples of prostate cancer, and divided the patients into high and low groups according to the methylation level of 10kb region.
The results found that only in the high methylation level group, rs11986220 was correlated with the expression of MYC and PVT1 In the hypomethylated group, there is no such correlation. This study has deepened people’s understanding of the role and mechanism of SNP in prostate cancer, and discovered for the first time the SNP sites that affect MYC expression in prostate cancer and their complex biological mechanisms, revealing how SNP sites affect transcription factors The combination with the genome, and this combination will be regulated by the structure of the 3D genome by DNA methylation, revealing that the changes in the epigenetics of the genome and the function of the genomic SNP locus synergistically affect the progression of prostate cancer.
The corresponding authors of the article are Professor Ren Shancheng of the Department of Urology, Changhai Hospital, Professor Wei Gonghong of Fudan University, and Professor He Housheng of the University of Toronto, Canada.
Reference: Ahmed, M.
, Soares, F.
, Xia, JH.
et al.
CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.
Nat Commun 12, 1781 (2021).
https:// doi.
org/10.
1038/s41467-021-21867-0
Whether these non-coding regions are only statistically associated with prostate cancer, or play a biological role, how to affect the occurrence and development of prostate cancer, there is little known in previous studies, and the mechanism is also unclear.
An in-depth understanding of the relationship between these SNP sites and the progression of prostate cancer is not only conducive to a deeper understanding of the role of SNP sites, but also a key step in transforming SNP sites from discovery to clinical application.
On March 19, Professor Ren Shancheng from Shanghai Changhai Hospital, Professor Wei Gonghong from Fudan University School of Basic Medicine and Affiliated Tumor Hospital (formerly at the University of Oulu, Finland), and Professor He Housheng from the University of Toronto in Canada teamed up in Nature Communications An article published in the journal CRISPRi screens reveals a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.
The team’s previous series of studies have determined that most of the prostate cancer-related risk SNPs are enriched in non-coding cis-forms on the genome.
Regulatory elements (risk-associated cis-regulatory elements, rCREs) region.In this paper, we have studied the functions of 260 rCRE regions in prostate cancer cell lines through CRISPRi screening, and found that different rCRE has different effects in different cell lines, and these different effects may be due to the expression on the genome.
The influence of genetic modification.
The author further conducted an in-depth study on the rCRE containing rs11986220 in the 8q24.
21 risk area of prostate cancer.
This region is adjacent to the oncogenes MYC and PVT1 in prostate cancer.
However, previous studies have not found an association between the SNP genotype and MYC expression in the 8q24.
21 risk area.
The researchers found that there are two CTCF transcription binding sites in the 10.
4kb (-10kb) and 2.
2kb (-2kb) regions upstream of the MYC gene promoter.
Previous reports have shown that CTCF has an important regulatory effect on the high-level structure of chromatin.
In prostate cancer, methylation in the 10kb upstream region of MYC promotes MYC expression, while methylation in the 2kb region inhibits MYC expression.
It is precisely because of the changes in the genomic methylation of the -10kb region of MYC in V16A cells and 22RV1 cells that affect the transcriptional binding of CTCF, which affects the remote regulation of MYC expression by the rs11986220 site, making the same SNP site There are different effects in different cells.
The authors found that the level of methylation in this region also regulates the expression of PVT1.
The author further verified this result in clinical samples of prostate cancer, and divided the patients into high and low groups according to the methylation level of 10kb region.
The results found that only in the high methylation level group, rs11986220 was correlated with the expression of MYC and PVT1 In the hypomethylated group, there is no such correlation. This study has deepened people’s understanding of the role and mechanism of SNP in prostate cancer, and discovered for the first time the SNP sites that affect MYC expression in prostate cancer and their complex biological mechanisms, revealing how SNP sites affect transcription factors The combination with the genome, and this combination will be regulated by the structure of the 3D genome by DNA methylation, revealing that the changes in the epigenetics of the genome and the function of the genomic SNP locus synergistically affect the progression of prostate cancer.
The corresponding authors of the article are Professor Ren Shancheng of the Department of Urology, Changhai Hospital, Professor Wei Gonghong of Fudan University, and Professor He Housheng of the University of Toronto, Canada.
Reference: Ahmed, M.
, Soares, F.
, Xia, JH.
et al.
CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.
Nat Commun 12, 1781 (2021).
https:// doi.
org/10.
1038/s41467-021-21867-0
