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Review
. 2013 May;253(1):290-303.
doi: 10.1111/imr.12048.

Exploring the RNA world in hematopoietic cells through the lens of RNA-binding proteins

Joan Yuan  1 , Stefan A Muljo
Affiliations
Review

Exploring the RNA world in hematopoietic cells through the lens of RNA-binding proteins

Joan Yuan et al. Immunol Rev. 2013 May.

Abstract

The discovery of microRNAs has renewed interest in posttranscriptional modes of regulation, fueling an emerging view of a rich RNA world within our cells that deserves further exploration. Much work has gone into elucidating genetic regulatory networks that orchestrate gene expression programs and direct cell fate decisions in the hematopoietic system. However, the focus has been to elucidate signaling pathways and transcriptional programs. To bring us one step closer to reverse engineering the molecular logic of cellular differentiation, it will be necessary to map posttranscriptional circuits as well and integrate them in the context of existing network models. In this regard, RNA-binding proteins (RBPs) may rival transcription factors as important regulators of cell fates and represent a tractable opportunity to connect the RNA world to the proteome. ChIP-seq has greatly facilitated genome-wide localization of DNA-binding proteins, helping us to understand genomic regulation at a systems level. Similarly, technological advances such as CLIP-seq allow transcriptome-wide mapping of RBP binding sites, aiding us to unravel posttranscriptional networks. Here, we review RBP-mediated posttranscriptional regulation, paying special attention to findings relevant to the immune system. As a prime example, we highlight the RBP Lin28B, which acts as a heterochronic switch between fetal and adult lymphopoiesis.

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Figures

Fig. 1
Fig. 1. Updated model of gene regulation that integrates RBPs and ncRNAs
A cell's fate is determined by its transcriptome and proteome. Its transcriptome and translatome is regulated by transcriptional and post-transcriptional networks. Here they are depicted as an integrated circuit that processes input (signal) to mediate an output, some form of cellular response (not depicted). For simplicity, post-translational and competing endogenous RNA networks are not depicted either. Chromatin regulators and transcription factors with the aid of lncRNAs control the accessibility and transcription rate of protein coding and non-coding genes while RBPs collaborate with ncRNAs to orchestrate the processing, transport, translation, and life-span of RNA transcripts. Since mRNA turnover can be slow, post-transcriptional regulation has evolved an important role in rapidly resetting the transcriptome in response to developmental and environmental cues that demand acute response not achievable by transcriptional regulation alone.
Fig. 2
Fig. 2. Divergent evolution of a let-7 miRNA family member to evade Lin28 binding
(A). Alignment of loop region sequences of all mouse pre-let-7 family members. (B). Alignment of loop region sequences of mouse pre-let-7c-2 orthologs in the indicated species. The box highlights the conserved absence of a consensus motif for Lin28 binding across vertebrates. Red: Canonical GGAG or GAAG motifs. Blue: motifs predicted not to bind Lin28. All sequences for alignments were obtained from miRBase (www.mirbase.org) (17).
Fig. 3
Fig. 3. Lin28b promotes fetal-like lymphopoiesis
(A). Model depicting how Lin28b and let-7 expression shifts between fetal and adult hematopoiesis. The immune system develops in waves during ontogeny, being initially populated by cells generated from fetal HSCs and later by cells derived from adult HSCs. Lin28b is highly expressed in fetal hematopoietic stem/progenitor cells (HSPCs) present in the fetal liver and thymus in humans and mice but is down-regulated in the neonate and undetectable in adult HSPCs. The expression of Lin28b correlates with the potential of fetal HSPCs for development of innate-like lymphocytes and inversely correlates with expression of mature let-7 family members. (B). Ectopic expression of Lin28 reprograms hematopoietic HSPCs from adult bone marrow, endowing them with the ability to mediate multi-lineage reconstitution that resembles fetal lymphopoiesis.
Fig. 4
Fig. 4. Lin28 controls multiple cellular processes post-transcriptionally via distinct mechanisms
Lin28 is a multi-functional RBP regulating growth and differentiation through inhibition of let-7 biogenesis as well as selective regulation of mRNA translation. Since let-7 is predicted to directly repress hundreds of target genes including Myc, Igf2bp2, Hmga2, IL-6, and K-ras, loss of mature let-7 expression could result in a dramatic effect on a cell's gene expression program. CLIP-seq has identified additional direct targets of Lin28 including its own mRNA, splicing factors and a collection of transcripts destined for translation in the ER. Knowing that Lin28 recognizes a consensus sequence and structure shared by many RNA molecules, we speculate that it could interact with lncRNAs as well to control many cellular processes. Dashed lines indicate indirect interactions, and dotted lines indicate hypothetical interactions that may be in effect depending on cellular context.
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References

    1. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–739. - PubMed
    1. Anokye-Danso F, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. 2011;8:376–388. - PMC - PubMed
    1. Miyoshi N, et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell. 2011;8:633–638. - PubMed
    1. Lim LP, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769–773. - PubMed
    1. Yoo AS, et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature. 2011;476:228–231. - PMC - PubMed

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