Hematopoietic Stem Cells; Stem Cells; Genomics; Systems Biology; Embryonic Stem Cells
Our long-term research interest is to understand how cell-fate decisions in stem cells are regulated at the molecular level. Our immediate focus is to define how the numerous components and pathways function coordinately to regulate self-renewal and commitment to differentiation in embryonic and hematopoietic stem cells, the two stem cell systems the lab is currently focusing on. For these studies we employ a broad-based strategy that integrates molecular, cellular and organismal approaches. The overall goal is to gain a comprehensive and deep understanding of fundamental cell fate choices.
Specialized Terms: Embryonic and somatic stem cells; Vertebrate development; Functional genomics; Systems biology
Extensive Research Description
Embryonic and adult stem cells hold great promise for regenerative medicine, tissue repair and gene therapy. Embryonic stem cells represent a transient cell population that exist during embryonic development and can give rise to all cell types present in an adult, while adult (somatic) stem cells are permanent cell populations dedicated to homeostatic production of mature cells in tissues such as blood, skin and gut. All stem cells must be able to balance self-renewal versus differentiation, regulate proliferation and cell death. Our long-term goal is to understand how cell-fate decisions in stem cells are regulated at the molecular level. We have recently developed a functional genomics approach to identify genetic mechanisms that control self-renewal in mouse embryonic stem cells.This approach utilizes short hairpin RNA (shRNA) loss-of-function techniques to down regulate a set of gene products whose expression patterns suggest self-renewal regulatory functions. We have applied this approach to a selected panel of candidate regulators and demonstrated that in addition to previously identified Nanog, Oct4 and Sox2 several other genes are required for efficient self-renewal of ES cells in vitro (Ivanova et al., Nature 2006). We are currently extending this screening strategy to genome-scale shRNA libraries.
Embryonic stem cells:
We have recently developed a functional genomics approach to identify genetic mechanisms that control self-renewal in embryonic stem cells. This approach utilizes short hairpin RNA (shRNA) loss-of-function techniques to downregulate a set of gene products whose expression patterns suggest self-renewal regulatory functions. We have applied this approach to a selected panel of candidate regulators and demonstrated that in addition to previously identified Nanog, Oct4 and Sox2 several other genes are required for efficient self-renewal of ES cells in vitro (Ivanova et al., Nature 2006). We are currently extending this screening strategy to genome-scale shRNA libraries.
Hematopoietic stem cells:
Hematopoiesis is organized as a hierarchy of cells of with decreasing self-renewal and differentiation potential. Long-term HSC, the most primitive cell in this hierarchy, can give rise to all blood lineages and has unlimited capacity to self-renew. LT-HSC produces short-term HSC which are still multipotent but are limited in self-renewal capacity. ST-HSC differentiates further into lineage-committed progenitor cells which are responsible for the large-scale production of mature blood cells. We have chosen global gene expression analysis in primary cells followed by functional characterization of candidate gene products as an approach towards the comprehensive identification of HSC regulatory mechanisms. To date we have performed transcriptional profiling of fetal and adult HSC using microarray-based technologies and have defined sets of genes that are specifically expressed in HSC but not in more differentiated compartments of the hematopoietic hierarchy(Ivanova, Science 2002). We currently study several candidate genes that are likely to function as key regulators of self-renewal and differentiation.
- Large-scale loss-of-function analyses to identify gene products that are required for self-renewal of mouse and human ES cells, and for commitment to specific lineages.
- In-depth characterization of previously identified regulators of self-renewal and differentiation.
- Computational modeling of lineage commitment.
- Single-cell gene expression analysis to define functional subsets within HSC.
- Functional analyses of candidate genes to identify gene-products that are necessary and/or sufficient for self-renewal of HSC both in vivo and in vitro.
Full List of PubMed Publications
- Wang Z, Gearhart MD, Lee YW, Kumar I, Ramazanov B, Zhang Y, Hernandez C, Lu AY, Neuenkirchen N, Deng J, Jin J, Kluger Y, Neubert TA, Bardwell VJ, Ivanova NB: A Non-canonical BCOR-PRC1.1 Complex Represses Differentiation Programs in Human ESCs. Cell Stem Cell. 2018 Feb 1; 2018 Jan 11. PMID: 29337181
- Mukai T, Crnković A, Umehara T, Ivanova NN, Kyrpides NC, Söll D: RNA-Dependent Cysteine Biosynthesis in Bacteria and Archaea. MBio. 2017 May 9; 2017 May 9. PMID: 28487430
- Mukai T, Vargas-Rodriguez O, Englert M, Tripp HJ, Ivanova NN, Rubin EM, Kyrpides NC, Söll D: Transfer RNAs with novel cloverleaf structures. Nucleic Acids Res. 2017 Mar 17. PMID: 28076288
- Mukai T, Englert M, Tripp HJ, Miller C, Ivanova NN, Rubin EM, Kyrpides NC, Söll D: Facile Recoding of Selenocysteine in Nature. Angew Chem Int Ed Engl. 2016 Apr 18; 2016 Mar 16. PMID: 26991476
- Mukai T, Englert M, Tripp HJ, Miller C, Ivanova NN, Rubin EM, Kyrpides NC, Söll D: [Facile Recoding of Selenocysteine in Nature]. Angew Chem Weinheim Bergstr Ger. 2016 Apr 18; 2016 Mar 15. PMID: 27440945
- Kumar I, Ivanova N: Moving Toward the Ground State. Cell Stem Cell. 2015 Oct 1. PMID: 26431178
- Zhang Y, Schulz VP, Reed BD, Wang Z, Pan X, Mariani J, Euskirchen G, Snyder MP, Vaccarino FM, Ivanova N, Weissman SM, Szekely AM: Functional genomic screen of human stem cell differentiation reveals pathways involved in neurodevelopment and neurodegeneration. Proc Natl Acad Sci U S A. 2013 Jul 23; 2013 Jul 8. PMID: 23836664
- Kloc A, Ivanova N: Chromatin and pluripotency: the MYSTerious connection. Cell Stem Cell. 2012 Aug 3. PMID: 22862937
- Oron E, Ivanova N: Cell fate regulation in early mammalian development. Phys Biol. 2012 Aug; 2012 Aug 7. PMID: 22871593
- Wang Z, Oron E, Nelson B, Razis S, Ivanova N: Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells. Cell Stem Cell. 2012 Apr 6. PMID: 22482508