An Emerging Role for isomiRs and the microRNA Epitranscriptome in Neovascularization

Reginald V C T van der Kwast, Paul H A Quax, A Yaël Nossent, Reginald V C T van der Kwast, Paul H A Quax, A Yaël Nossent

Abstract

Therapeutic neovascularization can facilitate blood flow recovery in patients with ischemic cardiovascular disease, the leading cause of death worldwide. Neovascularization encompasses both angiogenesis, the sprouting of new capillaries from existing vessels, and arteriogenesis, the maturation of preexisting collateral arterioles into fully functional arteries. Both angiogenesis and arteriogenesis are highly multifactorial processes that require a multifactorial regulator to be stimulated simultaneously. MicroRNAs can regulate both angiogenesis and arteriogenesis due to their ability to modulate expression of many genes simultaneously. Recent studies have revealed that many microRNAs have variants with altered terminal sequences, known as isomiRs. Additionally, endogenous microRNAs have been identified that carry biochemically modified nucleotides, revealing a dynamic microRNA epitranscriptome. Both types of microRNA alterations were shown to be dynamically regulated in response to ischemia and are able to influence neovascularization by affecting the microRNA's biogenesis, or even its silencing activity. Therefore, these novel regulatory layers influence microRNA functioning and could provide new opportunities to stimulate neovascularization. In this review we will highlight the formation and function of isomiRs and various forms of microRNA modifications, and discuss recent findings that demonstrate that both isomiRs and microRNA modifications directly affect neovascularization and vascular remodeling.

Keywords: A-to-I editing; RNA methylation; RNA modifications; angiogenesis; arteriogenesis; epitranscriptome; isomiRs; m6A; microRNA; neovascularization.

Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
MicroRNA biogenesis and alterations that induce isomiR formation or microRNA nucleotide modifications. Transcription of the microRNA containing gene forms the primary microRNA (pri-miR). Drosha cleaves the pri-miR to generate the precursor microRNA (pre-miR). The pre-miR cleaved by Dicer in the cytoplasm yielding the microRNA duplex. Either side of the duplex can be incorporated into the RNA-induced silencing complex (RISC) to become a functional mature microRNA. IsomiRs can be formed during microRNA biogenesis when Drosha or Dicer cleave in alternative locations, or when exonucleases or nucleotidyl transferases remove or add nucleotides to the 3′-end of the pre-miR or the mature microRNA. RNA nucleotide modifications with known or potential functional implications on microRNA biogenesis or functioning are shown in red with their ‘writers’ next to them.
Figure 2
Figure 2
Different types of isomiRs, their mechanism of formation and their potential functional effects. The sequence of miR-21 and some of its isomiRs are shown to exemplify the different isomiR types. In each case, the seed sequence is underlined (red if altered) and red nucleotides are due to nucleotidyl transferase activity. Relative to the canonical microRNA, 5′-isomiRs generally have an altered targetome due to shift in seed sequence whereas 3′-isomiRs can affect the microRNAs stability or turnover. Both types of isomiRs affect the length of the microRNA and can thus incur length-dependent effects.

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