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Stem Cell 2015;6(2) http://www.sciencepub.net/stem Stem Cell and Transcript Research Literatures Ma Hongbao 1, Margaret Young 2, Yang Yan 1 1 Brookdale Hospital, Brooklyn, New York 11212, USA; 2 Cambridge, MA 02138, USA [email protected] Abstract: The stem cell is the origin of an organism’s life that has the potential to develop into many different types of cells in life bodies. In many tissues stem cells serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a red blood cell or a brain cell. This article introduces recent research reports as references in the stem cell and transcript related studies. [Ma H, Young M, Yang Y. Stem Cell and Transcript Research Literatures. Stem Cell. 2015;6(2):56-72] (ISSN 1545-4570). http://www.sciencepub.net/stem. 8 Key words: stem cell; transcript; life; research; literature 1. Introduction REST (322) target genes. The majority of these The stem cell is the origin of an organism’s life CoREST targets do not contain known RE1 motifs. that has the potential to develop into many different Notably, these CoREST target genes do play important types of cells in life bodies. In many tissues stem cells roles in pluripotency networks, in modulating NSC serve as a sort of internal repair system, dividing identity and fate decisions and in epigenetic processes essentially without limit to replenish other cells as previously associated with both REST and CoREST. long as the person or animal is still alive. When a stem Moreover, we found that NSC-mediated cell divides, each new cell has the potential either to developmental transitions were associated primarily remain a stem cell or become another type of cell with with liberation of CoREST from promoters with a more specialized function, such as a red blood cell or transcriptional repression favored in less lineage- a brain cell. This article introduces recent research restricted radial glia and transcriptional activation reports as references in the related studies. favored in more lineage-restricted neuronal- oligodendrocyte precursors. Clonal NSC REST and The following introduces recent reports as CoREST gene manipulation paradigms further references in the related studies. revealed that CoREST has largely independent and Abrajano, J. J., I. A. Qureshi, et al. "Corepressor for previously uncharacterized roles in promoting NSC element-1-silencing transcription factor preferentially multilineage potential and modulating early neural fate mediates gene networks underlying neural stem cell decisions. fate decisions." Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16685-90. doi: 10.1073/pnas.0906917107. Akashi, K. "Cartography of hematopoietic stem cell Epub 2010 Sep 7. commitment dependent upon a reporter for The repressor element-1 (RE1) silencing transcription factor activation." Ann N Y Acad Sci. transcription factor/neuron-restrictive silencer factor 2007 Jun;1106:76-81. Epub 2007 Mar 14. (REST/NRSF) silences neuronal genes in neural stem A hierarchical hematopoietic developmental cells (NSCs) and nonneuronal cells through its role as tree has been proposed based on the result of a dynamic modular platform for recruitment of prospective purification of lineage-restricted transcriptional and epigenetic regulatory cofactors to progenitors. For more detailed mapping for RE1-containing promoters. In embryonic stem cells, hematopoietic stem cell (HSC) commitment, we the REST regulatory network is highly integrated with tracked the expression of PU.1, a major the transcriptional circuitry governing self-renewal and granulocyte/monocyte (GM)- and lymphoid-related pluripotency, although its exact functional role is transcription factor, from the HSC to the unclear. The C-terminal cofactor for REST, CoREST, myelolymphoid progenitor stages by using a mouse also acts as a modular scaffold, but its cell type- line harboring a knockin reporter for PU.1. This specific roles have not been elucidated. We used approach enabled us to find a new progenitor chromatin immunoprecipitation-on-chip to examine population committed to GM and lymphoid lineages CoREST and REST binding sites in NSCs and their within the HSC fraction. This result suggests that there proximate progenitor species. In NSCs, we identified a should be another developmental pathway independent larger number of CoREST (1,820) compared with of the conventional one with myeloid versus lymphoid 56 Stem Cell 2015;6(2) http://www.sciencepub.net/stem bifurcation, represented by common myeloid ability to target Oct-4 and to mimic a stem cell- progenitors and common lymphoid progenitors, specific activity. respectively. The utilization of the transcription factor expression as a functional marker might be useful to Bunaciu, R. P. and A. Yen "Activation of the aryl obtain cartography of the hematopoietic development hydrocarbon receptor AhR Promotes retinoic acid- at a higher resolution. induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription Behre, G., V. A. Reddy, et al. "Proteomic analysis of factor Oct4." Cancer Res. 2011 Mar 15;71(6):2371-80. transcription factor interactions in myeloid stem cell doi: 10.1158/0008-5472.CAN-10-2299. Epub 2011 development and leukaemia." Expert Opin Ther Jan 24. Targets. 2002 Aug;6(4):491-5. Retinoic acid (RA) is used to treat leukemia Recent results indicate that interactions of and other cancers through its ability to promote cancer transcription factors with other nuclear proteins play cell differentiation. Strategies to enhance the an important role in stem cell development, lineage anticancer effects of RA could deepen and broaden its commitment and differentiation in the haematopoietic beneficial therapeutic applications. In this study, we system, and the pathogenesis of myeloid leukaemias. describe a receptor cross-talk system that addresses High-throughput proteomics by mass spectrometric this issue. RA effects are mediated by RAR/RXR analysis of gel-separated proteins can identify multi- receptors that we show are modified by interactions protein complexes and changes in the expression of with the aryl hydrocarbon receptor (AhR), a protein multiple proteins simultaneously. This review functioning both as a transcription factor and a ligand- describes an application of proteomic methods (2D gel dependent adaptor in an ubiquitin ligase complex. electrophoresis (GE) and mass spectrometry (MS)), RAR/RXR and AhR pathways cross-talk at the levels which can be used to identify regulated protein targets of ligand-receptor and also receptor-promoter of transcription factors important in myeloid interactions. Here, we assessed the role of AhR during differentiation and leukaemia. This global high- RA-induced differentiation and a hypothesized throughput functional proteomics approach could lead convergence at Oct4, a transcription factor believed to to new insights into the network of protein-protein maintain stem cell characteristics. RA upregulated interactions and target proteins involved in myeloid AhR and downregulated Oct4 during differentiation of stem cell development and leukaemia as well as HL-60 promyelocytic leukemia cells. AhR provide new targets for rational pathogenesis-based overexpression in stable transfectants downregulated therapies of leukaemia and cancer. Oct4 and also decreased ALDH1 activity, another stem cell-associated factor, enhancing RA-induced Brehm, A., K. Ohbo, et al. "Synergism with germ line differentiation as indicated by cell differentiation transcription factor Oct-4: viral oncoproteins share the markers associated with early (CD38 and CD11b) and ability to mimic a stem cell-specific activity." Mol late (neutrophilic respiratory burst) responses. AhR Cell Biol. 1999 Apr;19(4):2635-43. overexpression also increased levels of activated Raf1, Activation of transcription by Oct-4 from which is known to help propel RA-induced remote binding sites requires a cofactor that is differentiation. RNA interference-mediated restricted to embryonal stem cells. The adenovirus knockdown of Oct4 enhanced RA-induced E1A protein can mimic the activity of this stem cell- differentiation and G(0) cell-cycle arrest relative to specific factor and stimulates Oct-4 activity in parental cells. Consistent with the hypothesized differentiated cells. Here we characterize the Oct-4- importance of Oct4 downregulation for differentiation, E1A interaction and show that the E1A 289R protein parental cells rendered resistant to RA by biweekly harbors two independent Oct-4 binding sites, both of high RA exposure displayed elevated Oct4 levels that which specifically interact with the POU domain of failed to be downregulated. Together, our results Oct-4. Furthermore, we demonstrate that, like E1A, suggested that therapeutic effects of RA-induced the human papillomavirus E7 oncoprotein also leukemia differentiation depend on AhR and its ability specifically binds to the Oct-4 POU domain. E7 and to downregulate the stem cell factor Oct4. Oct-4 can form a complex both in vitro and in vivo. Expression of E7 in differentiated cells stimulates Oct- Chittka, A., J. Nitarska, et al. "Transcription factor 4-mediated transactivation from distal binding sites. positive regulatory domain 4 (PRDM4) recruits Moreover, Oct-4, but not other Oct factors, is active protein arginine
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