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Beyond mRNA: The role of non-coding RNAs in normal and aberrant hematopoiesis

https://doi.org/10.1016/j.ymgme.2017.07.008Get rights and content

Highlights

  • Define the current classification schemes of non-coding RNA and examine trends and challenges facing these schemes.

  • Examine the cellular roles of non-coding RNA, with an emphasis on hematopoiesis.

  • Examine the contribution of pseudogenes, retrotransposons, sORFs and micropeptides on hematopoiesis.

Abstract

The role of non-coding Ribonucleic Acids (ncRNAs) in biology is currently an area of intense focus. Hematopoiesis requires rapidly changing regulatory molecules to guide appropriate differentiation and ncRNA are well suited for this. It is not surprising that virtually all aspects of hematopoiesis have roles for ncRNAs assigned to them and doubtlessly much more await characterization. Stem cell maintenance, lymphoid, myeloid and erythroid differentiation are all regulated by various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and various transposable elements within the genome. As our understanding of the many and complex ncRNA roles continues to grow, new discoveries are challenging the existing classification schemes. In this review we briefly overview the broad categories of ncRNAs and discuss a few examples regulating normal and aberrant hematopoiesis.

Introduction

It has been proposed that < 2% of the human genome is translated into proteins. However, somewhere between 70% [1] to over 90% [2] of the genome is transcribed, and over 60% of these transcripts are processed [1]. The RNA that does not encode conventional proteins is referred to collectively as non-coding RNA (ncRNA) and encompasses transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA) and small cajan body-specific RNA (scaRNA), piwi-interacting RNA (piRNA), miRNA and lncRNA amongst others (see Table 1). While relatively recent advances in deep sequencing technology has shed light on the full extent of ncRNA expression it has long been recognized ncRNA is critical in genomics. For instance, rRNA and tRNA are essential in protein synthesis [3], and messenger RNA (mRNA) splicing and nuclear organization require snRNAs and snoRNAs [4]. The recent documentation of the extensive contribution of ncRNA transcripts of all sizes and types has resulted in new and constantly evolving categories. As our understanding grows, new nomenclature will most likely develop to better categorize ncRNAs by functionality. Recently, a number of predicted ncRNAs have been documented that encode proteins, either as micropeptides hidden as short open reading frames (sORFs) within ncRNAs, or due to read-throughs of stop codon sequences [5], adding further confusion around the broad coding and non-coding classification scheme. Here we will define the current classifications of ncRNAs and briefly discuss the emerging roles they play on various aspects of hematopoiesis.

Section snippets

MicroRNA (miRNAs)

miRNAs consist of 21–24 bases and are involved in regulation of post-transcriptional gene expression regulation and RNA silencing. The first example was documented in 1993 in Caenorhabditis elegans when a 21 nucleotide RNA was shown to inhibit the Lin 14 transcript [6]and was subsequently named Lin4. Since then, hundreds of miRNAs have been identified and the list continues to grow [7]. However, the name microRNA was not applied until 2001 [8].

As summarized in Fig. 1, these short RNA sequences

Piwi-interacting RNAs (piRNAs)

While microRNAs tend to span sizes 21–24 nucleotides, piRNAs are slightly larger at 26–31 nucleotides, and collectively form the largest class of small ncRNAs in animal cells [66]. They form RNA-protein complexes with the piwi class of proteins (see Fig. 2 for summary). In comparison with miRNAs they lack sequence conservation and possess increased complexity. Currently, the most characterized cellular role of piRNAs is in epigenetic and post-translational silencing of retrotransposons and

Long non-coding RNA (lncRNAs)

Long non-coding RNAs are defined as a large class of RNAs with sequences longer than 200 nucleotides which differentiates them from classically defined small nuclear RNAs (such as miRNAs, snoRNAs, etc.). This classification is somewhat ambiguous as some classically defined small nuclear RNAs are also > 200 nucleotides, thus specific recognition of transcripts > 200 nucleotides as lncRNA has only been applied rigorously to newly recognized transcripts [68].

The number of lncRNA transcripts greatly

Pseudogenes

Pseudogenes are genes derived from another gene that show various degrees of sequence redundancy from the original “parental” gene. Due to redundancy, the pseudogene is not required for the survival of the organism and is consequently under little selective pressure, which allows multiple mutations to accumulate [101]. These mutations lead to loss of the original function, either through loss of gene expression or ability to code protein, however many pseudogenes have evolved important cellular

Retrotransposons

Over half the human genome is comprised of repetitive sequences derived from pseudogenes and retrotransposons [104] (see Table 2). There are two broad categories of transposable elements (TEs) based on how they copy themselves from one location to another in the genome (summarized in Fig. 4) [104]. Class 2 transposable elements are more ancient and have been referred to as DNA transposons or “jumping genes”, the discovery of which lead to the nobel prize in Physiology or Medicine for Barbara

sORFs and micropeptides

A potentially translatable sequence of in-frame sense codons beginning with a start codon and ending with a stop codon is known as on open reading frame (ORF). Translatable ORFs are the sequences of mRNA that give rise to its principle protein, often referred to as the coding DNA sequence (CDS). sORFs are distinguished from all other ORFs by size, and like longer ORFs not all are translated or even translatable [5]. The theoretical minimal size of sORFs is two codons consisting of a start and

Concluding remarks

Despite seemingly exponential growth in our characterization of new roles for ncRNA in hematopoiesis, our understanding is far from complete. However, it is clear these molecules are deeply embedded in the regulatory processes of hematopoiesis. From miRNAs to lncRNAs virtually all aspects of transcription, translation, localization, stabilization, structural integrity, complex formation, differentiation and evolution are intricately balanced with cell type and differentiation specific accuracy.

Acknowledgments

Dr. Sakamoto is funded by NIH R01DK107286 and Mark Wilkes is funded by USHHS Ruth L. Kirschstein Institutional National Research Service Award # T32 DK098132.

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