Chemical Modifications and Their Role in Long Non-coding RNAs

  • Sindy Zander
  • Roland Jacob
  • Tony GutschnerEmail author


The advent of next-generation sequencing technologies (NGS) in the last two decades combined with the elaborate implementation of algorithms as well as huge leaps in computing power shed light on the complex world of nucleic acids besides DNA. Tantalizingly, about 70–90% of the human genome is transcribed, but only ~2% is translated into proteins. Therefore, non-translated transcripts represent the overwhelming majority of the transcriptome, and they received the much-needed attention in the past decade. Several studies demonstrated the involvement of long noncoding RNAs (lncRNAs) in a vast number of cellular signaling pathways. Moreover, they play an active role in the regulation of gene expression utilizing varied ways of molecular mechanisms. Recently, the sophisticated application of NGS techniques paved the way for the transcriptome-wide characterization of different types of posttranscriptional chemical modifications of RNAs. These non-genomically encoded alterations expand the wide variety of the transcriptome even further. They influence important properties of transcripts, i.e., localization and stability, thereby modulating key cellular processes like translation, gene regulation, and metabolism. Despite great advances in the field and huge gains in knowledge about RNA modifications, most of the way to a comprehensive understanding needs still to be mastered.

In this chapter, the three most common RNA modifications, namely, N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ), will be the center of attention. At first we will give an overview of writers, readers, and erasers of those modifications, and then we will briefly summarize methods for their detection. Ultimately, we will introduce modifications on selected, cancer-related lncRNAs.


Cancer lncRNA Noncoding RNA Epitranscriptome 5-Methylcytosine N6-methyladenosine Pseudouridine 







Alpha-ketoglutarate-dependent dioxygenase alkB homolog 5


Acute lymphoblastic leukemia


Aly/REF export factor


Acute myeloid leukemia


Acute nonlymphoblastic leukemia


Antisense non-coding RNA in the INK4 locus


Alu-mediated CDKN1A/p21 transcriptional regulator


AU-rich element


5-Azacytidine-mediated RNA immunoprecipitation


N3-CMC-enriched pseudouridine sequencing


Cross-linking-induced mutation site


Cross-linking-induced truncation site


N-Cyclohexyl-N′-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate


Chronic myeloid leukemia


Corepressor of RE1-silencing transcription factor


Colorectal cancer


DICER1 antisense RNA 1


Dyskerin pseudouridine synthase 1


Deleted in lymphocytic leukemia 2-like


DNA methyltransferase-2


Eukaryotic initiation factor 3


Eukaryotic initiation factor 4E


Epithelial-mesenchymal transition


Fat mass- and obesity-associated protein


Growth arrest-specific 5




Glioblastoma stem-like cells


Histone H3 lysine-27


Histone H3 lysine-4


Heterogeneous nuclear ribonucleoprotein U


Heterogeneous nuclear ribonucleoprotein A2/B1


Heterogeneous nuclear ribonucleoprotein C


HOX antisense intergenic RNA


Homeobox C/D


Human antigen R


Individual-nucleotide-resolution cross-linking and immunoprecipitation


Long non-coding RNA


LRRC75A antisense RNA1


Lysine-specific demethylase 1A








MAGI2 antisense RNA 3


Metastasis-associated lung adenocarcinoma transcript 1


MALAT1-associated small cytoplasmic RNA


Methionine adenosyltransferase 2A


Myelodysplastic syndrome


M6A-specific methylated RNA immunoprecipitation sequencing


Methyltransferase-like protein




Myeloproliferative neoplasm


Messenger RNA


Mass spectrometry




Non-coding RNA


Nuclear paraspeckle assembly transcript 1


Nuclear-enriched abundant transcript 2


Next-generation sequencing


Non-small cell lung cancer


NOP2/Sun RNA methyltransferase family member




Photo-cross-linking-assisted m6A sequencing


Polycomb group


PIWI-interacting RNA


Polycomb-repressive complex 2


Posttranslational modification


Pseudouridine synthase


Pseudouridylate synthase 7-like


Pseudouridylate synthase-like 1


Pvt1 oncogene


Retinoic acid receptor


RNA-binding protein


RE1-silencing transcription factor


RNA-binding motif protein 15


RNA methyltransferase


RNA 7SK small nuclear


Ribonuclease P RNA component H1


RNA pseudouridylate synthase domain containing


Ribosomal RNA


Reverse transcription-polymerase chain reaction


S-Adenosyl methionine


Site-specific cleavage and radioactive labeling followed by ligation-assisted extraction and thin-layer chromatography


Small interfering RNA


Small nucleolar RNA host gene


Small nucleolar RNA


Small nuclear RNA


Spen family transcriptional repressor


Steroid receptor RNA activator


Steroid receptor RNA activator protein


ST7 antisense RNA 1


Telomerase RNA component


Transfer RNA


TruB pseudouridine synthase family member


Taurine upregulated 1


Untranslated region


Vir-like m6A methyltransferase associated


Wilms’ tumor 1-associating protein


X-inactivation center


X-inactive-specific transcript


YTH domain-containing protein


YT521-B homology domain family


ZNFX1 antisense RNA 1



We apologize to all scientists whose important work could not be cited in this review due to space constraints. The authors wish to thank Monika Hämmerle for critical reading of the manuscript. Research in the Gutschner lab is supported by funds from the intramural Wilhelm-Roux Program of the Medical Faculty, Martin-Luther-University Halle-Wittenberg.

Author Contributions

Sindy Zander and Roland Jacob wrote the manuscript and prepared figures and tables. Tony Gutschner conceptualized and edited the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Faculty of Medicine, Martin-Luther-University Halle-WittenbergHalle (Saale)Germany

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