The maintenance of stem cell identity, lineage commitment and cell differentiation is assured by specific gene expression patterns temporally and spatially organized by regulatory processes. These processes involve transcription factors that affect the lineage-specific gene expression programs and epigenetic mechanisms which contribute to their stabilization. The importance of the establishment of specific gene expression patterns during development and adult life is well acknowledged. However, the mechanisms and pathways underlying cell fate choices are still incompletely defined.
Polycomb (PcGs) proteins are transcriptional repressors, which have recently received much attention as modulators of stem cell differentiation in mammals.1-3 PcGs control transcriptional programs that preserve the epigenetic memory and identity of each cell type throughout the lifetime of organisms.4,5 PcGs proteins are evolutionarily conserved and exist in at least two separate protein complexes; the PcG repressive complex 1 (PRC1) and the PcG repressive complex 2–4 (PRC2/3/4). PRC1 is a large complex including several proteins such as YY1, BMI1, HPH1–3, HPC proteins and RING1A-1B.6,7 The core components of PRC2/3/4 are EZH2, various isoforms of EED, SUZ12 and the histone-binding proteins RbAp48/46.8 Although the composition of PcG complexes can vary among different cell types and organisms,9,10 they all modify chromatin structure by covalent modification of histone proteins.3,11,12 PRC2 catalyzes trimethylation of lysine 27 on histone H3 (H3K27me2/3), while PRC1 mono-ubiquitinates histone H2A on lysine 119 (H2AK119Ub1).13,14
Genome-wide mapping of PcGs and chromatin marks revealed the coexistence of repressive H3K27me3 and activating H3 lysine 4 tri-methylation (H3K4me3) marks at a number of genomic loci. These loci, termed “bivalent domains,” were found in mouse and human ES cells as well as in a broad range of adult stem cells, including hematopoietic stem cells (HSCs).9,15-17 Bivalent domains keep developmentally regulated and tissue-specific genes transcriptionally poised.16-22 The co-localization of these marks appears well-centered around the genes’ transcriptional start site; the H3K4me3 modification localizes ± 1 Kb around the transcriptional start site whereas H3K27me3 affects a larger area of ± 2.5 Kb.19,21,23 Bivalent domains can bind to both the PRC1 and PRC2 complexes at the same time or exclusively to the PRC2 complex.24 Indeed, bivalent domains are divided into two classes depending on the PcG complex that binds them. The “PRC1-positive” bivalent domains are evolutionarily conserved, more likely retain H3K27me3 upon differentiation and account for developmental regulator genes. “PRC1-negative” bivalent domains, exclusively bound by PRC2, are less conserved, retain H3K27me3 poorly and correspond to membrane protein genes or genes with unknown functions.24 Genes presenting bivalent domains show low or intermediate expression levels in ES cells and HSCs. When ES cells or HSCs are induced to differentiate, bivalent domains are generally resolved into either repressive H3K27me3 or activating H3K4me3 marks.18,19 However, which molecular mechanisms drive the resolution of the bivalent domains and their inheritance through cell divisions is still an open question. The recent discovery of histone demethylases adds new complexity. Among the Jumonji C domain-containing proteins, Jarid1 de-methylates H3K4me2/3, whereas JMJD3 and UTX de-methylate H3K27me2/3.25-32 These interactions may integrate the activity of PcG and Trithorax complexes. They modulate the inhibition or activation of genes required for lineage-specific determination.31,33,34
On the other hand, CDK1 and CDK2 phosphorylate EZH2 at threonine 350 during the S phase of cell cycle.35,36 At target loci in cells, this modification activates EZH2 binding to PRC2 recruiters (such as non-coding RNAs).37 This novel regulatory mechanism may be relevant for the maintenance of H3K27me3 marks through cell division.35,36
Overexpression of EZH2 and its aberrant recruitment on target gene sites have been implicated in cancer initiation and progression. In prostate cancer, overexpression of EZH2 can be driven by the upregulation of MYC protein via transcriptional (direct targeting of EZH2 promoter) and post-transcriptional (downregulation miR-26a and -26b) mechanisms.38 In acute myeloid leukemia cells, Evi1 physically interacts with EZH2 and recruits EZH2 and other PcG proteins to the PTEN promoter region.39,40 This induces histone modifications (H3K27me3), which represses PTEN transcription and activates the PI3KAKT/mTOR signaling pathway. This mechanism also contributes to leukemogenesis.39,40 Interestingly, Evi1 is expressed in: 10% of cases of acute myeloid leukemias associated with extremely poor prognosis.41
We initially identified the Nuclear factor I-A (NFI-A) as a post-transcriptional miR-223 target, which was functionally involved in a regulatory circuitry that directed human granulopoiesis.42
NFI-A belongs to the Nuclear Factor I (NFI) family of transcriptional factors. This family is composed of four independent genes (NFI-A, -B, -C and X). Its members are involved in the cell growth, replication of adenoviral DNA, oncogenic processes and disease state.43 NFI-A binds as a dimer or heterodimer, along with other members of the NF-I family or other transcriptional factors, to the dyad symmetric consensus sequence TTGGC(N5)GCCAA on DNA.43 Binding sites for NFIs have been identified in genes expressed in virtually every tissue of vertebrates.
In human primary hematopoietic stem/progenitor cells (HSC/HPCs), upregulation of NFI-A levels induces differentiation along the erythroid lineage, while its downregulation shifts HSC/HPC fate toward the granulocytic lineage. Therefore, NFI-A acts as a regulator of human hematopoietic stem cell/progenitor lineage choice.44-46
Dissecting the epigenetic mechanisms that regulate NFI-A gene expression in HSC/HPCs, we observed, that in human ES cells, the NFI-A promoter region is marked by an H3K27me3/H3K4me3 bivalent domain.20 We showed that, in hematopoietic cells, the resolution of the NFI-A bivalent domain is required to direct granulopoiesis or erythropoiesis.46 During granulocytic differentiation of primary HSC/HPCs and myeloid precursor cell lines, NFI-A gene silencing is caused by the recruitment of PcG proteins YY1 and Suz12. These trigger the resolution of the bivalent domain (H3K27me3 increased, whereas H3K4me3 decreased) and induce nearby heterochromatin formation. A stable Suz12-knockdown in myeloid progenitor HL60 cells impeded the bivalent domain resolution, increased the expression levels of NFI-A and impaired retinoic acid (RA)-induced granulocytic differentiation.46
YY1 is the only PcG protein possessing a sequence-specific element (CCATnTT) for DNA binding, where it can recruit other PRCs.47 A bio-informatic analysis of NFI-A promoter region showed that it is rich in consensus YY1 binding sites and GAGAG recurrent motifs, recently confirmed as Polycomb Responsive Elements (PREs).7,48
PcGs also own RNA binding properties and ncRNAs may be required for PcG recruitment to DNA, promoting chromatin remodeling and transcriptional gene silencing (TGS).49,50
We then hypothesized that a leading role in PRC promoter targeting is played by non-coding RNA (ncRNA) or by RNAi machinery components. We found that, in HL60 cells undergoing RA-induced granulocytic differentiation, YY1 associates with Dicer1.46 These two proteins share a localization at the nuclear periphery, a site of preferential heterochromatin localization.51 Moreover, YY1, Suz12, Dicer1 and transiently Argonaute (Ago) 1 accumulate on NFI-A promoter to form a repressive complex.46 Accordingly, the silencing of both Dicer1 and Ago1 in HL60 cells significantly impaired the RA-induced bivalent domain resolution on NFI-A promoter. This affected NFI-A-expression and cell differentiation response, thus supporting a direct role of these RNAi components in the transcriptional regulation of this gene.
These findings are also in agreement with emerging data attributing to component of RNAi machinery, such as Dicer and Ago proteins, a direct role in determining chromatin modifications. Dicer2 and Ago2 were found associated to chromatin and contribute to transcriptional regulation in Drosophila.52 In Schizosaccharomyces pombe, Dicer1 physically associates with chromatin, providing direct evidence for RNAi-mediated heterochromatin formation in cis at centromeric repeats.53 Moreover, Giles et al.54 have shown that RNAi components Dicer1 and Ago2 are recruited at the 16 Kb chicken β-globin locus. The chromatin landscape of this locus is altered in siDicer1- and siAgo2–6C2 cells (lowered H3K9me2 levels, increased H4acetylation and H3K9 acetylation levels). Ahlenstiel et al.55 also investigated the subcellular co-localization of Ago proteins with promoter-targeted siRNAs during TGS of SIV and HIV-1 infection. Their study revealed that Ago1 co-localizes with siRNA in the nucleus at the sites of TGS, while Ago2 co-localized with siRNA in the inner nuclear envelope. Overall, these and our results directly implicate Dicer1 and Ago proteins in epigenetic marking, heterochromatin formation and transcriptional activity of target genes, although some discrepancy regarding the specific role of Ago1 and Ago2 proteins still exists. How Polycomb and RNAi components can be guided to the controlled genomic loci is still an open question. We hypothesized that a newly discovered nuclear roles of small or long non-coding RNA also involve their direct binding of target genes genomic loci.
Emerging evidence suggest that noncoding RNA (ncRNAs), have important regulatory functions in the control of transcriptional programs. Besides determining the post-transcriptional gene silencing of their targets, ncRNAs may act as sensors and integrators of a wide variety of transcriptional responses and, probably, epigenetic events too.56
MicroRNA (miRNAs) genes transcribe small ncRNAs ~22 nucleotides long, which repress the expression of proteins involved in development, differentiation, proliferation and apoptosis. They mainly act through limited base-pairing to complementary mRNA sequences. Proper miRNAs' functioning requires their assembly into an RNA-induced silencing complex (RISC), which includes Dicer, members of the Argonaute protein family, the RNA binding protein TRBP and other proteins. In a RISC, miRNAs serve as the specificity guide for target mRNA recognition.57,58 MiRNA expression is tissue-specific and highly regulated according to the cell’s developmental lineage and stage.57,58
MiRNAs are also present in integrated transcriptional regulatory circuitries. They can change the expression levels of lineage-specific transcription factors and/or members of the epigenetic machinery and are, in turn, regulated by these factor activities.59,60
Recently it has been shown that miRNAs expression and activity can be also modulated by the cell type- and allele-specific expression of snpRNAs (single nucleotide polymorphism RNAs), which represent allele-specific “decoy” targets of miRNAs. MiRNA may act as intrinsic regulatory components of snpRNA networks that contribute to maintenance of the epigenetic state in cells.61
MiRNAs are therefore ideal intermediate in transcriptional regulation, as base pairing with target sequences can account for specificity and ensure the robustness of cell fate decision.
Growing evidence indicates that miRNAs also have nuclear functions. The canonical miRNA biogenesis implies Exportin 5-mediated transfer of the pre-miRNA from nucleus to cytoplasm.57,58,62 However, a number of studies indicate that miRNAs may shuttle between cytoplasm and nucleus. This was first revealed in HeLa cells for miR-29b, which displays a mostly nuclear localization, determined by a 3' terminal hexanucleotide.63 Further studies have shown that both CRM1 and Importin 8 contribute to intracellular miRNA transport.64,65 These shuttling proteins can conduct nuclear importation for both miRNA and Ago proteins. Accordingly, a number of mature miRNAs were identified by microarray and RT-qPCR analysis in purified nuclei of colon cancer cells and in the nucleolus of rat myoblasts.66,67 A clear demonstration of the nuclear distribution of miRNAs came from a deep-sequencing analysis of small RNAs in nuclear and cytoplasmic fractions derived from a human nasopharyngeal carcinoma cell line.68 Three hundred miRNAs were identified both in the nucleus and in the cytoplasm, whereas 39 miRNAs displayed a preferential nuclear localization.68 Overall, the nuclear distribution of miRNAs seems to be solid evidence. Indeed, besides their cytoplasmic activity, miRNAs may associate with RISC components in the nucleus to regulate transcription, contributing to both transcription activation and repression of genes. However, the presence of miRNAs in a transcription regulating molecular complex on the promoter of target genes and the biological relevance of miRNA-mediate transcriptional regulation was not analyzed in depth.
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