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Functions of heterogeneous nuclear ribonucleoproteins in stem cell potency and differentiation - PubMed

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Functions of heterogeneous nuclear ribonucleoproteins in stem cell potency and differentiation

Qishan Chen et al. Biomed Res Int. 2013.

Abstract

Stem cells possess huge importance in developmental biology, disease modelling, cell replacement therapy, and tissue engineering in regenerative medicine because they have the remarkable potential for self-renewal and to differentiate into almost all the cell types in the human body. Elucidation of molecular mechanisms regulating stem cell potency and differentiation is essential and critical for extensive application. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are modular proteins consisting of RNA-binding motifs and auxiliary domains characterized by extensive and divergent functions in nucleic acid metabolism. Multiple roles of hnRNPs in transcriptional and posttranscriptional regulation enable them to be effective gene expression regulators. More recent findings show that hnRNP proteins are crucial factors implicated in maintenance of stem cell self-renewal and pluripotency and cell differentiation. The hnRNPs interact with certain sequences in target gene promoter regions to initiate transcription. In addition, they recognize 3'UTR or 5'UTR of specific gene mRNA forming mRNP complex to regulate mRNA stability and translation. Both of these regulatory pathways lead to modulation of gene expression that is associated with stem cell proliferation, cell cycle control, pluripotency, and committed differentiation.

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Figures

Figure 1
Figure 1

Structure of hnRNPs with multiple modules. Except hnRNP E, K, and U, all other reported hnRNP family proteins contain one or more RRM domains, the structural base responsible for the RNA/ssDNA binding. Instead of RRM domain, hnRNP E and K contain three copies of KH domains. Since KH domain displays relatively weaker RNA/ssDNA binding affinity, it is believed that several copies of KH domains within a given protein are required for achieving greater RNA/ssDNA binding affinity and specificity. RGG repeats domain is the only RNA-binding domain identified in hnRNP U responsible for RNA/ssDNA binding.

Figure 2
Figure 2

Functions of hnRNP A/B family in SMC differentiation. hnRNP A2/B1 and hnRNP A1 seem to regulate SMC specific gene expression and cell differentiation at two transcriptional levels. hnRNP A2/B1 or hnRNP A1 activates or modulates the transcriptional machinery of SMC specific genes by upregulating another SMC differentiation mediator, Cbx3, or SMC transcription factors and/or co-activators such as SRF, myocardin, and MEF2c, respectively, resulting in SMC differentiation gene expression. hnRNP A1 or hnRNP A2/B1 can also directly regulate SMC differentiation gene expression through SRF binding elements or other specific binding sites within SMC specific gene promoter region.

Figure 3
Figure 3

hnRNPs in r15-LOX mediated mitochondria degradation during erythoid differentiation and maturation. hnRNP K functions as a switch for r15-LOX and c-Src gene expression in the early phase of erythoid differentiation, the former is an important mediator regulating erythoid differentiation and erythrocyte maturation and the latter is a tyrosine kinase that phosphorylates hnRNP K activity and forms a feedback loop to regulate r15-LOX gene expression during the late phase of erythoid differentiation or erythrocyte maturation. Importantly, hnRNP K itself is cleaved and inactivated by caspase-3 during erythoid progenitor cell differentiation.

Figure 4
Figure 4

hnRNPs in regulation of hemoglobin expression in erythoid differentiation. Three hnRNP proteins, hnRNP D, E1, and E2, have been suggested to play an important role in the hemoglobin synthesis. All three hnRNP proteins regulate α- or β-globin mRNA levels through stabilising both mRNAs by directly binding to CU-rich elements within 3′UTR of these genes.

Figure 5
Figure 5

Roles of hnRNPs in the impaired granulocytic differentiation of BCR/ABL transformed myeloid progenitor cells. Both hnRNP E2 and FUS function as the downstream regulators of BCR/ABL oncoprotein and have been implicated in chronic myelogenous leukemia by preventing granulocytic differentiation from myeloid progenitor cells through inhibiting G-CSFR and blocking G-CSF signaling, which finally disrupt the normal myeloid cell differentiation or maturation pathway, resulting in myeloid progenitor cell accumulation abnormally in the bone marrow and circulation.

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