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Tsankov, Alexander M.

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Tsankov

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Alexander M.

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Tsankov, Alexander M.

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2012 - 20156

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Author's Publications: search.filters.isAuthorOfPublication.20adc539-1b4f-458e-b6dc-bee78ea7c1f7

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Now showing 1 - 6 of 6
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    Transcription factor binding dynamics during human ESC differentiation
    (2015) Tsankov, Alexander M.; Gu, Hongcang; Akopian, Veronika; Ziller, Michael; Donaghey, Julie; Amit, Ido; Gnirke, Andreas; Meissner, Alexander
    Summary Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage specific behavior of selected factors. In addition to the orchestrated remodeling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signaling effectors, and the epigenome during human embryonic stem cell differentiation.
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    Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells
    (Elsevier BV, 2013) Gifford, Casey A.; Ziller, Michael; Gu, Hongcang; Trapnell, Cole; Donaghey, Julie; Tsankov, Alexander M.; Shalek, Alex K.; Kelley, David Roy; Shishkin, Alexander A.; Issner, Robbyn; Zhang, Xiaolan; Coyne, Michael; Fostel, Jennifer L.; Holmes, Laurie; Meldrim, Jim; Guttman, Mitchell; Epstein, Charles; Park, Hongkun; Kohlbacher, Oliver; Rinn, John; Gnirke, Andreas; Lander, Eric; Bernstein, Bradley; Meissner, Alexander
    Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions.
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    A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation
    (The Rockefeller University Press, 2015) Chetty, Sundari; Engquist, Elise; Mehanna, Elie; Lui, Kathy O.; Tsankov, Alexander M.; Melton, Douglas
    Driving human pluripotent stem cells (hPSCs) into specific lineages is an inefficient and challenging process. We show that a potent Src inhibitor, PP1, regulates expression of genes involved in the G1 to S phase transition of the cell cycle, activates proteins in the retinoblastoma family, and subsequently increases the differentiation propensities of hPSCs into all three germ layers. We further demonstrate that genetic suppression of Src regulates the activity of the retinoblastoma protein and enhances the differentiation potential of hPSCs across all germ layers. These positive effects extend beyond the initial germ layer specification and enable efficient differentiation at subsequent stages of differentiation.
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    An improved ScoreCard to assess the differentiation potential of human pluripotent stem cells
    (2015) Tsankov, Alexander M.; Akopian, Veronika; Pop, Ramona; Chetty, Sundari; Gifford, Casey A.; Daheron, Laurence; Melton, Douglas; Tsankova, Nadejda M.; Meissner, Alexander
    Research on human pluripotent stem cells has been hampered by the lack of a standardized, quantitative, scalable assay of pluripotency. We have previously described an assay called ScoreCard that used gene expression signatures to quantify differentiation efficiency. Here we report an improved version of the assay based on qPCR that enables faster, more quantitative assessment of functional pluripotency. We provide an in-depth characterization of the revised signature panel through embryoid body and directed differentiation experiments as well as a detailed comparison to the teratoma assay. We also show that the improved ScoreCard enables applications such as screening of small molecules, genetic perturbations and assessment of culture conditions. Beyond stem cell applications, this approach can in principle be extended to other cell types and lineages.
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    Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells
    (2015) Liao, Jing; Karnik, Rahul; Gu, Hongcang; Ziller, Michael; Clement, Kendell; Tsankov, Alexander M.; Akopian, Veronika; Gifford, Casey A.; Donaghey, Julie; Galonska, Christina; Pop, Ramona; Reyon, Deepak; Tsai, Shengdar Q.; Mallard, William; Joung, J. Keith; Rinn, John; Gnirke, Andreas; Meissner, Alexander
    DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Here we inactivated all three catalytically active DNA methyltransferases in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing to further investigate their roles and genomic targets. Disruption of DNMT3A or DNMT3B individually, as well as of both enzymes in tandem, creates viable, pluripotent cell lines with distinct effects on their DNA methylation landscape as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome the immediate lethality, we generated a doxycycline (DOX) responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1 mutant lines. However, DOX-mediated repression of the exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death. Our data provide a comprehensive characterization of DNMT mutant ESCs, including single base genome-wide maps of their targets.
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    Epigenomics and Chromatin Dynamics
    (BioMed Central, 2012) Akopian, Veronika; Chan, Michelle; Clement, Kendell; Galonska, Christina; Gifford, Casey; Lehtola, Elizabeth; Liao, Jing; Samavarchi-Tehrani, Payman; Sindhu, Camille; Smith, Zachary; Tsankov, Alexander M.; Webster, Jamie Orme; Zhang, Yingying; Ziller, Michael; Meissner, Alexander
    A report of the 'Joint Keystone Symposium on Epigenomics and Chromatin Dynamics', Keystone, Colorado, 17-22 January 2012. This year's Joint Keystone Symposium on Epigenomics and Chromatin Dynamics was one of the largest Keystone meetings to date, reflecting the excitement and many developments in this area. Richard Young opened the meeting by giving a historic overview before sharing more detailed insights from his recent work in describing the role of the lysine demethylase Lsd1 in mouse embryonic stem (ES) cell differentiation. He also set the broader stage and highlighted the excitement concerning recent advances in epigenetic drugs such as the new bromodomain inhibitors.