Reactivation of tumour suppressor in breast cancer by enhancer switching through NamiRNA network

Abstract

Dysfunction of Tumour Suppressor Genes (TSGs) is a common feature in carcinogenesis. Epigenetic abnormalities including DNA hypermethylation or aberrant histone modifications in promoter regions have been described for interpreting TSG inactivation. However, in many instances, how TSGs are silenced in tumours are largely unknown. Given that miRNA with low expression in tumours is another recognized signature, we hypothesize that low expression of miRNA may reduce the activity of TSG related enhancers and further lead to inactivation of TSG during cancer development. Here, we reported that low expression of miRNA in cancer as a recognized signature leads to loss of function of TSGs in breast cancer. In 157 paired breast cancer and adjacent normal samples, tumour suppressor gene GPER1 and miR-339 are both downregulated in Luminal A/B and Triple Negative Breast Cancer subtypes. Mechanistic investigations revealed that miR-339 upregulates GPER1 expression in breast cancer cells by switching on the GPER1 enhancer, which can be blocked by enhancer deletion through the CRISPR/Cas9 system. Collectively, our findings reveal novel mechanistic insights into TSG dysfunction in cancer development, and provide evidence that reactivation of TSG by enhancer switching may be a promising alternative strategy for clinical breast cancer treatment.

SARS-CoV-2 RNA elements share human sequence identity and upregulate hyaluronan via NamiRNA-enhancer network

“… 21 However, we discovered that miRNAs located in the nucleus were capable of activating gene expression by targeting enhancers and termed them as "Nuclear activating miRNAs (NamiRNAs)". 22 , 23 Consistent with our findings, Sharp and colleagues deciphered the interaction between super-enhancers (SEs) and miRNA networks. 24 NamiRNAs not only activate adjacent genes by targeting the enhancer where miRNA is located, but also activate distant genes by targeting other enhancers.…”

“… 22 Recent study showed that miR-339 can regulate tumor suppressor gene transcription by targeting enhancers in the human genome. 23 Therefore, we speculated that the interaction between nucleotide sequence of SARS-CoV-2 and human genome might function in SARS-CoV-2 infection and its pathogenicity during the clinical progression of COVID-19. Considering that the shortest regulatory RNAs are 19–23 nt miRNAs, 36 we first analyzed the sequence similarity between the genome of SARS-CoV-2 (accession number NC_045512) and human (GRCh38/hg38) with the following conditions: (1) length range of sequences are greater than 20 bp; (2) matching rate is 100%.…”

“… 14 Previously, we revealed that miRNA located in the nucleus can activate tumor suppressor gene expression. 23 The fragments containing HIS in SARS-CoV-2 are predicted to form potential pre-miRNA structure, indicating HIS may function as miRNA-like RNAs. Further bioinformatic analysis showed that many HIS-SARS2 and enhancers cascade regulating genes are associated with cytokines, which may in part explain why most severe COVID-19 patients are characterized clinically by a cytokine storm, the main cause for ARDS leading to death.…”

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

“…Epigenetics, including DNA methylation, has been implicated in causing several diseases such as neuroblastoma [ 12 ], breast cancer [ 13 ], colon cancer [ 14 ], and liver cancer [ 14 ], via silencing tumor suppressor genes [ 15 ] and inducing oncogenes [ 12 ]. Recent studies have shown that the alternation of DNA methylation is a leading cause of colon cancer and being considered as biomarkers [ 16 ].…”

FBP1 /miR-24-1/enhancer axis activation blocks renal cell carcinoma progression via Warburg effect

“…In our previous work ( 13 ), we revealed a type of miRNA whose DNA loci are overlapped with enhancer region can activate the expression of target genes through the corresponding enhancers (named NamiRNA), in particular, FBP1 was activated by the enhancer-overlapping NamiRNA-24-1 in a manner dependent on enhancer activity in HEK293T cells. Thus, we proposed a NamiRNA-enhancer-gene activation network to better understand the miRNA activation phenomenon ( 14 – 16 ). Other findings also support the critical crosstalk between enhancers and their overlapping miRNAs, highlighting important tissue-specific cancer biomarkers ( 17 , 18 ).…”