Esteban Mazzoni, PhD
Assistant Professor, Dept. of Biology
PhD 2006 - New York University
Stem cells, Transcription Factors, neuronal subtypes, morphogens
New York University
Department of Biology
1009 Silver Center
100 Washington Square East
New York, NY 10003-6688
Fax: (212) 995-4015
Embryonic stem cell (ESC) differentiation has the potential to be instrumental in cell based therapies, in vitro disease modeling and chemical screens. To fulfill those expectations, ESCs have to be directed at high efficiency to disease relevant cell types, either by the application of extracellular signals or direct programming by forced expression of transcription factors. Therefore, our long term goal is to understand how extracellular signals and transcription factors control cell fate and apply that knowledge to differentiate ESC into disease relevant neuronal cell types.
Mechanisms of direct neuronal programming
Recent advances in cell programming demonstrated that terminal cell fate can be established by a handful of selector transcription factors. To understand cell differentiation and to gain control of cell fate during direct programming, it is necessary to rationalize how selector factors recognize their genomic targets and control gene expression. The plastic genetic state of ESC is particularly receptive to the programming activity of transcription factors. Therefore, the expression of few factors programs ESC into neurons at high efficiency allowing us to apply biochemical interrogation techniques to study gene expression, physiological properties, chromatin status and genomic occupancy of transcription factors. Our data suggests that programming transcription factors synergize to activate cell-specific transcriptional programs. Thus, instead of “selector genes,” “selector cassettes” are the functional units controlling cell fate. We hope to derive rules that allow the rational design of programming selector cassettes.
Hox gene function during motor neuron differentiation
The central nervous system is composed by a myriad of neuronal types and subtypes that are essential for proper connectivity and function. Therefore, successful in vitro differentiation protocols to be applied either for cell based therapies or disease modeling should produce neurons with defined generic and subtype identity. However, the subtype identity is rarely controlled during ESC directed differentiation or cellular programming. During in vivo and in vitro differentiation, members of the Hox family of transcription factors impose subtype identity and control motor neuron (MN) connectivity. Thus, understanding how Hox genes interact and synergize with MN resident factors to control subtype identity is the key to manipulating MN identity. Based on phenotypic characterization, expression analysis and ChIP-seq of Hox genes during in vitro MN differentiation, we plan to identify the enhancer structure at Hox binding sites and to establish the minimal set of cofactors and molecular logic required for Hox gene activity in MNs. The final measure of our understanding of Hox gene activity will be the direct generation of precise MN subtypes at will.
Generation of cells relevant for human neurodegenerative diseases
In vitro differentiation of human ESC has the potential to serve as a “humanized” platform to study complex neurodegenerative diseases. Current protocols based on human stem cells are inefficient and/or take several weeks and are thus inappropriate for large-scale phenotypic characterization and drug screens. We take advantage of sets of transcription factors that program mouse ESC to two types of human neurons with different sensitivities to Amyotrophic Lateral Sclerosis (ALS). These cells would become an in vitro human model to investigate intrinsic resistance to ALS. Comparing the transcriptomic and epigenomic landscapes of these two cell types under normal and stressed conditions might yield insight into new approaches to treat neurodegenerative diseases. In the future, both cell types can be the substrate for chemical screens to identify molecules that enhance MN survival.
- “Embryonic Stem cell system to study transcription factor binding during development.” Esteban O. Mazzoni, Shaun Mahony, Michelina Iacovino, Carolyn A. Morrison, George Mountoufaris, Michael Closser, Warren A. Whyte, Richard A. Young, Michael Kyba, David K. Gifford and Hynek Wichterle. Nat Methods. 2011 Nov 13;8(12):1056-8. PMID: 22081127
- Feedback from Rhodopsin protein controls rhodopsin exclusion in Drosophila R8 photoreceptors”. Daniel Vasiliauskas, Esteban O. Mazzoni, Simon G. Sprecher, Robert J. Johnston Jr., Preetmoninder Lidder, Nina Vogt, and Claude Desplan. Nature. 2011 Oct 9;479(7371):108-12. PMID: 21983964
- “An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming.” Gabut M, Samavarchi-Tehrani P, Wang X, Slobodeniuc V, O'Hanlon D, Sung HK, Alvarez M, Talukder S, Pan Q, Mazzoni EO, Nedelec S, Wichterle H, Woltjen K, Hughes TR, Zandstra PW, Nagy A, Wrana JL, Blencowe BJ. Cell. 2011 Sep 30;147(1):132-46. PMID: 21924763
- “Wnt Signaling Specifies and Patterns Intestinal Endoderm”. Richard I Sherwood, Rene Maehr, Esteban O. Mazzoni, and Douglas A Melton. Mech Dev. 2011 Aug 10. PMID: 21854845
- “Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis.” Shaun Mahony&, Esteban O. Mazzoni&, Scott McCuine, Richard A. Young , Hynek Wichterle, and David K. Gifford. Genome Biology. 2011 Jan 13;12(1) (PMID: 21232103) & Equal contribution. PMID: 21232103
- “Mir-17-3p Controls Spinal Neural Progenitor Patterning by Regulating Olig2/Irx3 Cross-repressive Loop.” Jun-An Chen, Yuan-Ping Huang, Esteban O. Mazzoni, G. Christopher Tan, Jiri Zavadil, and Hynek Wichterle. Neuron. 2011 Feb 24;69(4):721-35. PMID: 21338882