TETRAMER | Predicted master regulators

Predicted master regulators

 TETRAMER has been used to predict master transcription factor regulators over a variety of cell fate transition cases like retinoids-driven Neuronal cell differentiation; OSKM-driven cell reprogramming as well as B-limphoma/primary macrophage transdifferentiation. Herein, the references to the articles from which the transcriptomes information has been used for TF prediction are available, as well as their relevant master regulator regulatory programs as predicted by TETRAMER.

 In addition, TETRAMER has been used for evaluating TFs' cell fate transition capacity over a comparative study of transcriptomes assessed over more than 300 cell type/tissues. The results of these large study can be explored herein.



Genome Res. 2016 Nov;26(11):1505-1519. Epub 2016 Sep 20.

Abstract: Reconstructed cell fate-regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Mendoza-Parra MA, Malysheva V, Mohamed Saleem MA, Lieb M, Godel A, Gronemeyer H.

Abstract: Cell lineages, which shape the body architecture and specify cell functions, derive from the integration of a plethora of cell intrinsic and extrinsic signals. These signals trigger a multiplicity of decisions at several levels to modulate the activity of dynamic gene regulatory networks (GRNs), which ensure both general and cell-specific functions within a given lineage, thereby establishing cell fates. Significant knowledge about these events and the involved key drivers comes from homoge- neous cell differentiation models. Even a single chemical trigger, such as the morphogen all-trans retinoic acid (RA), can induce the complex network of gene-regulatory decisions that matures a stem/precursor cell to a particular step within a given lineage. Here we have dissected the GRNs involved in the RA-induced neuronal or endodermal cell fate specification by integrating dynamic RXRA binding, chromatin accessibility, epigenetic promoter epigenetic status, and the transcrip- tional activity inferred from RNA polymerase II mapping and transcription profiling. Our data reveal how RA induces a network of transcription factors (TFs), which direct the temporal organization of cognate GRNs, thereby driving neuro- nal/endodermal cell fate specification. Modeling signal transduction propagation using the reconstructed GRNs indicated critical TFs for neuronal cell fate specification, which were confirmed by CRISPR/Cas9-mediated genome editing. Overall, this study demonstrates that a systems view of cell fate specification combined with computational signal transduction mod- els provides the necessary insight in cellular plasticity for cell fate engineering. The present integrated approach can be used to monitor the in vitro capacity of (engineered) cells/tissues to establish cell lineages for regenerative medicine.

Nat Commun. 2014;5:3197. doi: 10.1038/ncomms4197.

Foxd1 is a mediator and indicator of the cell reprogramming process.

Koga M, Matsuda M, Kawamura T, Sogo T, Shigeno A, Nishida E, Ebisuya M.

Abstract: It remains unclear how changes in gene expression profiles that establish a pluripotent state are induced during cell reprogramming. Here we identify two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of gene expression programme changes during reprogramming. Knockdown of Foxd1 or Foxo1 reduces the number of iPSCs, and the double knockdown further reduces it. Knockout of Foxd1 inhibits downstream transcriptional events, including the expression of Dax1, a component of the autoregulatory network for maintaining pluripotency. Interestingly, the expression level of Foxd1 is transiently increased in a small population of cells in the middle stage of reprogramming. The transient Foxd1 upregulation in this stage is correlated with a future cell fate as iPSCs. Fate mapping analyses further reveal that >95% of iPSC colonies are derived from the Foxd1-positive cells. Thus, Foxd1 is a mediator and indicator of successful progression of reprogramming.

Cell Rep. 2013 Apr 25;3(4):1153-63. doi: 10.1016/j.celrep.2013.03.003. Epub 2013 Mar 28.

C/EBPa induces highly efficient macrophage transdifferentiation of B lymphoma and leukemia cell lines and impairs their tumorigenicity.

Rapino F, Robles EF, Richter-Larrea JA, Kallin EM, Martinez-Climent JA, Graf T.

Abstract: Earlier work demonstrated that the transcription factor C/EBPa can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPa is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPaER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPa was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPa induction also impaired the cells’ tumorigenicity. Likewise, C/EBPa efficiently converted a lymphoblastic leukemia B cell line into macro-phage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced by C/EBPa to trans-differentiate into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy for treating B cell malignancies.

Aging Cell 2014; 13(3):487-96. doi: 10.1111/acel.12197

Senescence-secreted factors activate Myc and sensitize pretransformed cells to TRAIL-induced apoptosis.

Vjetrovic J; Shankaranarayanan P; Mendoza-Parra MA; Gronemeyer H

Abstract: Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome (SAS) supports cell transformation, we asked whether SAS factor(s) would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pretransformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling of CMS-exposed pretransformed cells indicated a paracrine autoregulatory loop of SAS factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with and depended on MYC upregulation and massive changes in gene regulation. Senescent cell-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL , thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL-sensitizing effect on pretransformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) will not only provide a mechanistic insight into the acquisition of TRAIL sensitivity but may lead to novel concepts for apoptogenic therapies of premalignant and TRAIL-resistant tumors.

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Stem Cell Reports. 2015 Nov 10;5(5):763-75.

A systematic approach to identify candidate transcription factors that control cell identity.

D'Alessio AC, Fan ZP, Wert KJ, Baranov P, Cohen MA, Saini JS, Cohick E, Charniga C, Dadon D, Hannett NM, Young MJ, Temple S, Jaenisch R, Lee TI, Young RA.

Abstract: Hundreds of transcription factors (TFs) are expressed in each cell type, but cell identity can be induced through the activity of just a small number of core TFs. Systematic identification of these core TFs for a wide variety of cell types is currently lacking and would establish a foundation for understanding the transcriptional control of cell identity in development, disease, and cell-based therapy. Here, we describe a computational approach that generates an atlas of candidate core TFs for a broad spectrum of human cells. The potential impact of the atlas was demonstrated via cellular reprogramming efforts where candidate core TFs proved capable of converting human fibroblasts to retinal pigment epithelial-like cells. These results suggest that candidate core TFs from the atlas will prove a useful starting point for studying transcriptional control of cell identity and reprogramming in many human cell types.

Similarity with known cell types' master TFs' networks

While TETRAMER can help you identify master regulators implicated in the cell fate transition process under study, their relevance in a defined cell/tissue system program remains to be further explored. For that we have made possible to compare the list of predicted master TFs with the collection of gene regulatory networks assessed over ~300 cell/tissue types on the human system.



Tutorial

A rather intuitive overview of how to use TETRAMER for reconstructing GRNs, as well as to predict master TF regulators.


Downloads

A direct access to the TETRAMER app (Cytoscape environment), as well as to the required gene regulatory networks collected from major publicly available efforts.


Publications

TETRAMER has been originally designed for predicting master regulators on retinoids-driven neuronal/endodermal cell fate transitions.