Long and short non-coding RNAs as regulators of hematopoietic differentiation

Abstract

Genomic analyses estimated that the proportion of the genome encoding proteins corresponds to approximately 1.5%, while at least 66% are transcribed, suggesting that many non-coding DNA-regions generate non-coding RNAs (ncRNAs). The relevance of these ncRNAs in biological, physiological as well as in pathological processes increased over the last two decades with the understanding of their implication in complex regulatory networks. This review particularly focuses on the involvement of two large families of ncRNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of hematopoiesis. To date, miRNAs have been widely studied, leading to a wealth of data about processing, regulation and mechanisms of action and more specifically, their involvement in hematopoietic differentiation. Notably, the interaction of miRNAs with the regulatory network of transcription factors is well documented whereas roles, regulation and mechanisms of lncRNAs remain largely unexplored in hematopoiesis; this review gathers current data about lncRNAs as well as both potential and confirmed roles in normal and pathological hematopoiesis.

Figure 1

Two models of the hierarchical hematopoiesis process. Hematopoietic cell differentiation proceeds by successive hierarchical maturation steps. (A) Pluripotent hematopoietic stem cells (HSC) give rise to multipotential progenitors (MPP) leading to common lymphocyte progenitors (CLP) and common myeloid progenitors (CMP). CLPs directly generate cells of the immune system. CMPs give rise to megakaryocyte-erythroid progenitors (MEP) and granulocyte-macrophage progenitors (GMP); (B) The alternative model differs by the involvement of an intermediate lymphoid-primed multipotential progenitor (LMPP) to generate GMP and CMP. Both models lead to the production of differentiated hematopoietic cells (M, monocyte; G, granulocytes; E, Erythrocyte; MK, megakaryocyte; T and B, lymphocytes; NK, natural killers DC, dendritic cells).

Figure 2

Schematic representation of different non coding RNAs.

Figure 3

Partial representation of the network involving microRNAs (mir) and regulatory proteins in hematopoiesis. Network was built using Cytoscape 2.8.2 software [36]. Transcription factors are represented as green rectangles, miRNAs as red diamonds, and other proteins as grey ellipses. Arrows depict relationships: arrows (activation), T (inhibition), circle (undetermined/binding). RARB, Retinoic acid receptor B, ARF, Alternate Reading Frame, CSF1R, colony-stimulating factor 1 receptor; BCR-ABL, breakpoint cluster region-Abelson; CBFB, Core-binding factor subunit beta; IL6, interleukine 6; LMO2, LIM domain only 2; HBA1, hemoglobin A1; KLFD, Krüppel like factor D; RUNX1, Runt-related transcription factor 1; CEBPA, CCAAT/enhancer-binding protein alpha; CEBPB, CCAAT/enhancer-binding protein beta; GM-CSF, granulocyte macrophage-colony stimulating factor; NFIA, nuclear factor I-A.

Figure 4

Scheme of regulations involving lncRNAs and miRNAs, influencing transcription, maturation or translation processes and example of interaction between lncRNAs, DNA, proteins and miRNAs. Blue arrows correspond to physiological maturation of RNA. Green lines correspond to inhibition processes and dotted black lines correspond to variable regulations (positive or negative depending on the mechanism). (−) Negative effect; (+/−) negative or positive effect.