Role of RNA modifications in blood development and regeneration

Abstract

Blood development and regeneration require rapid turnover of cells, and ribonucleic acid (RNA) modifications play a key role in it via regulating stemness and cell fate regulation. RNA modifications affect gene activity via posttranscriptional and translation-mediated mechanisms. Diverse molecular players involved in RNA-modification processes are abundantly expressed by hematopoietic stem cells and lineages. Close to 150 RNA chemical modifications have been reported, but only N6-methyl adenosine (m⁶A), inosine (I), pseudouridine (Ψ), and m1A-a handful-have been studied in-cell fate regulation. The role of RNA modification in blood diseases and disorders is an emerging field and offers potential for therapeutic interventions. Knowledge of RNA-modification and enzymatic activities could be used to design therapies in the future. Here, we summarized the recent advances in RNA modification and the epitranscriptome field and discussed their regulation of blood development and regeneration.

Figure 1-

Schematic depicting RNA species, RNA modification, and diverse blood cell types regulated by epitranscriptomic regulation. Diverse RNA types (inner circle) are modified with numerous RNA modifications (outer circle), adding a second layer of information that contributes to cell fate decisions (Octagon).

Figure 2-

m⁶A editing machinery and cellular outcomes of m⁶A RNA modification. RNA methylation is added co-transcriptionally by ‘writer enzymes’ that form the MTAse complex. ‘Eraser’ enzymes, ALKBH5 and FTO, are RNA demethylases that edit RNA modifications. A large family of ‘reader’ proteins binds to RNA methylations and regulates RNA translation, RNA granule, and RNA stability.

Figure 3-

Waddington paradigm depicting hematopoietic stem cell and various lineage fate regulation via RNA modifications. HSC functions are regulated by epitranscriptome, and lineage fate decisions are influenced by RNA modifications. Each color represents fate restriction as the cell progressively takes up an identity. A combination of RNA modifications is predicted to regulate transcriptome at various stages of cell fate decisions.

Figure 4-

RNA modification-mediated cell fate regulation in normal and disease contexts. Levels of RNA modifications are regulated by RNA-modifying enzymes. In normal cells, these molecular players are controlled by various signaling and environmental cues. In diseased conditions such as cancers, the mutations in these mechanisms are derailed.