Up–to–date on the evidence linking miRNA-related epitranscriptomic modifications and disease settings. Can these modifications affect cross-kingdom regulation?

Figures & data

Table 1. Summary of studies reporting a crosstalk between RNA modifications and miRNAs in disease settings

RNA modification	Disease/condition		ncRNA	Enzyme	Effects	Outcomes	Ref
m^6A	Acute Ischemic Stroke (AIS)	miR-335		METTL3	METTL3-mediated m6A modification upregulates mature miR-335 generation, which targets Erf1	METTL3/miR-335/Erf1 axis contributes to SG formation, which may reduce AIS injury in the early stage	[18]
	Liver fibrosis	miR-350		METTL3	ASIC1a upregulates the expression of mature miR-350, which targets SPRY2 and activates the PI3K/AKT and ERK pathways	Promotion of HSC activation and liver fibrosis	[97]
	Diabetic retinopathy	miR-25-3p		METTL3	regulation of miR-25-3p/PTEN/Akt signaling cascade in a DGCR8-dependent manner	Alleviated high-glucose induced RPE cell apoptosis and pyroptosis, and promoted cell proliferation	[98]
	Colistin-induced nephrotoxicity	miR-873-5p		METTL3	METTL3 positively modulates miR-873-5p mature process, thereby regulating the Keap1/Nrf2 pathway	Anti-oxidative stress and anti-apoptotic role	[99]
	Lung cancer	miR-143-3p		METTL3	METTL3 facilitates the biogenesis of miR-143-3p, which targets the 3’UTR of VASH1 to inhibit its expression	Overexpression of METTL3 is associated with increased invasion capability and angiogenesis of cancer cells	[100]
	Hepatocellular carcinoma	miR-126		METTL14	METTL14 interacts with DGCR8 and promotes the processing of pri-miR-126 in an m6 A-dependent manner m6A marks enhanced the recognition of pri-miR126 by DGCR8 and the subsequent processing to mature miRNA	METTL14 may be involved in HCC metastasis, acting as a negative regulator	[101]
	Pancreatic cancer	let-7a-5p, miR-17-5p		METTL3/ METTL14	1) Raised METTL3 /METTL14 levels are accompanied by increased methylation in cancer tissues and serum vs normal; 2) m6A modified miRNAs have a reduced ability to inhibit mRNAs	Methylated miRNAs could become cancer biomarkers	[102]
		miR-25-3p		METTL3	METTL3 promotes the maturation of miR-25-3p, which suppresses PHLPP2, resulting in the activation of oncogenic AKT-p70S6K signaling	Overexpression of METTL3 associates with cancer development and progression	[103]
	Colorectal cancer	let-7a-5p, miR-17-5p		METTL3/ METTL14	1) Raised METTL3 /METTL14 levels are accompanied by increased methylation in cancer tissues and serum vs normal; 2) m6A modified miRNAs have a reduced ability to inhibit mRNAs	Methylated miRNAs could become cancer biomarkers	[102]
		miR-1246		METTL3	METTL3 promotes the maturation of pri-miR-1246, resulting in the downregulation of SPRED2 and inhibition of the MAPK pathway	Overexpression of METTL3 promotes cell migration and invasion	[104]
	Bladder cancer	miR-221/222		METTL3	METTL3 promotes the maturation of pri-miR221/222, resulting in the reduction of PTEN	Overexpression of METTL3 promotes cancer proliferation	[105]
m^5C	Pancreatic cancer and colorectal cancer	miR-200c-3p, miR-21-3p		NSUN2	1) Raised NSUN2 levels were accompanied by increased methylation in cancer tissues and serum vs normal; 2) m5C modifications in miR-200c-3p did not affect its ability to inhibit mRNAs	Methylated miRNAs could become cancer biomarkers	[102]
	Glioblastoma multiforme	miR-16-5p, miR-181a-5p, miR-181b-5p, miR-181d-5p, miR-210-3p, miR-451a, miR-193a-5p		DNMT3A/ AGO4	m5C in miR-181a-5p and miRNA-451a abolishes their tumor suppressor functions	Poorer prognosis in GBM patients	[106]
2′-O-methylation	Lung cancer	miR-21-5p		HENMT1	1) HENMT1 was significantly increased in lung cancer tissues compared to non-cancerous lung tissues; 2) differential 3′-terminal 2′Ome was shown for miR-21-5p in non-small cell lung cancer (NSCLC)	Methylated miRNAs could become cancer biomarkers	[107]
Uridylation	Osteosarcoma	miR-24, miR-29a		TUT1	Upregulation of miR-24 and miR-29a by TUT1 reduced PPARgamma and SREBP-1c expression	Reduced lipogenesis and tumor progression	[108]
	Breast cancer	let-7a, let-7f		LIN28	Wnt–b-catenin pathway enhances HRAS and HMGA2 protein expression through Lin28 activation and let-7 repression	Proliferation of cancer stem cells	[109]
	Head and Neck cancer	let-7 family		LIN28B	Down-regulation of the let-7 family by Lin28b results in enhanced HMGA2, CCND2, IGF1R, and IGF2BP2 levels	Enhanced tumor progression	[110].
m^7G	Lung and colon cancer	let-7-5p, miR-125a-5p, miR-92b-3p		METTL1	METTL1-dependent m7G promotes the processing of tumor-suppressive miRNAs, including the let-7 family reducing the levels of HMGA2	Reduced cell migration	[15]

AGO4, Argonaute RISC catalytic component 4; CCND2, cyclin D2; DNMT3A, DNA (cytosine-5)-methyltransferase 3A; Erf1, eukaryotic translation termination factor; GBM, Glioblastoma multiforme; HMGA2, High mobility group protein HMGI-C; HRAS, GTPase HRas; IGF1R, insulin like growth factor 1 receptor; IGF2BP2, insulin like growth factor 2 mRNA binding protein 2; LIN28B, lin-28 homolog B; m⁵C, 5-methylcytosine; m⁶A, N6-Methyladenosine; m⁷G, 7-Methylguanosine; METTL1, (guanine-N(7)-)-methyltransferase 1; METTL3, N6-adenosine-methyltransferase catalytic subunit; METTL14, N(6)-adenine-specific methyltransferase; NSUN2, Myc-induced SUN domain-containing protein; PHLPP2, PH domain leucine-rich repeat protein phosphatase 2; PPARgamma, peroxisome proliferator-activated receptor gamma; SREBP-1c, Sterol regulatory element-binding protein 1; TUT, terminal uridylyl transferase 1; VASH1, vasohibin-1.

Figure 1. Epitranscriptomic modifications in miRNAs. Schematic representation of miRNA biogenesis in mammals and plants. HEN-1 is a methyltransferase that adds a methyl group to the ribose of the last nucleotide (represented as R) of small RNAs (sRNAs). This methylation protects the 3ʹ-end of sRNAs from uridylation activity and subsequent degradation. Not all miRNA biogenesis mechanisms are depicted. Frequently reported miRNA modifications, along with representative examples, are shown on the right bottom corner