Esteban Mazzoni

Embryonic stem cell (ESC) differentiation has the potential to be instrumental in cell based therapies and 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. Preliminary 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. However, the subtype identity is rarely controlled during ESC directed differentiation or cellular programming. 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. 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.

Date of these PubMed search results: March 24 2020
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1. Cell Reprogramming: The Many Roads to Success.
   Annu Rev Cell Dev Biol (2019 Oct 6) PMID: 31340126
   Aydin B, Mazzoni EO
2. Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons.
   Elife (2019 Jun 3) PMC6594754 free full-text archive
   An D, Fujiki R, Iannitelli DE, Smerdon JW, Maity S, Rose MF, Gelber A, Wanaselja EK, Yagudayeva I, Lee JY, Vogel C, Wichterle H, Engle EC, Mazzoni EO
3. Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes.
   Nat Neurosci (2019 Jun) PMC6556771 free full-text archive
   Aydin B, Kakumanu A, Rossillo M, Moreno‑Estelles M, Garipler G, Ringstad N, Flames N, Mahony S, Mazzoni EO
4. cAMPr: A single-wavelength fluorescent sensor for cyclic AMP.
   Sci Signal (2018 Mar 6) PMC5863242 free full-text archive
   Hackley CR, Mazzoni EO, Blau J
5. Deconvolving sequence features that discriminate between overlapping regulatory annotations.
   PLoS Comput Biol (2017 Oct) PMC5663517 free full-text archive
   Kakumanu A, Velasco S, Mazzoni E, Mahony S
6. Corrigendum: CTCF-mediated topological boundaries during development foster appropriate gene regulation.
   Genes Dev (2017 Aug 15) PMC5647941 free full-text archive
   Narendra V, Bulajic M, Dekker J, Mazzoni EO, Reinberg D
7. RNA localization is a key determinant of neurite-enriched proteome.
   Nat Commun (2017 Sep 19) PMC5605627 free full-text archive
   Zappulo A, van den Bruck D, Ciolli Mattioli C, Franke V, Imami K, McShane E, Moreno‑Estelles M, Calviello L, Filipchyk A, Peguero‑Sanchez E, Muller T, Woehler A, Birchmeier C, Merino E, Rajewsky N, Ohler U, Mazzoni EO, Selbach M, Akalin A, Chekulaeva M
8. CTCF-mediated topological boundaries during development foster appropriate gene regulation.
   Genes Dev (2016 Dec 15) PMC5238725 free full-text archive
   Narendra V, Bulajic M, Dekker J, Mazzoni EO, Reinberg D
9. A Multi-step Transcriptional and Chromatin State Cascade Underlies Motor Neuron Programming from Embryonic Stem Cells.
   Cell Stem Cell (2017 Feb 2) PMC5291817 free full-text archive
   Velasco S, Ibrahim MM, Kakumanu A, Garipler G, Aydin B, Al‑Sayegh MA, Hirsekorn A, Abdul‑Rahman F, Satija R, Ohler U, Mahony S, Mazzoni EO
10. Iterative Role of Notch Signaling in Spinal Motor Neuron Diversification.
    Cell Rep (2016 Jul 26) PMC4975379 free full-text archive
    Tan GC, Mazzoni EO, Wichterle H
11. CRISPR-dCas9 and sgRNA scaffolds enable dual-colour live imaging of satellite sequences and repeat-enriched individual loci.
    Nat Commun (2016 May 25) PMC4894952 free full-text archive
    Fu Y, Rocha PP, Luo VM, Raviram R, Deng Y, Mazzoni EO, Skok JA
12. CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation.
    Science (2015 Feb 27) PMC4428148 free full-text archive
    Narendra V, Rocha PP, An D, Raviram R, Skok JA, Mazzoni EO, Reinberg D
13. Evolving Hox activity profiles govern diversity in locomotor systems.
    Dev Cell (2014 Apr 28) PMC4024207 free full-text archive
    Jung H, Mazzoni EO, Soshnikova N, Hanley O, Venkatesh B, Duboule D, Dasen JS
14. An integrated model of multiple-condition ChIP-Seq data reveals predeterminants of Cdx2 binding.
    PLoS Comput Biol (2014 Mar) PMC3967921 free full-text archive
    Mahony S, Edwards MD, Mazzoni EO, Sherwood RI, Kakumanu A, Morrison CA, Wichterle H, Gifford DK
15. Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals.
    Nat Neurosci (2013 Sep) PMC3799941 free full-text archive
    Mazzoni EO, Mahony S, Peljto M, Patel T, Thornton SR, McCuine S, Reeder C, Boyer LA, Young RA, Gifford DK, Wichterle H
16. Neuroscience. Mapping neuronal diversity one cell at a time.
    Science (2013 Aug 16) PMID: 23950522
    Wichterle H, Gifford D, Mazzoni E
17. Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity.
    Nat Neurosci (2013 Sep) PMC3820498 free full-text archive
    Mazzoni EO, Mahony S, Closser M, Morrison CA, Nedelec S, Williams DJ, An D, Gifford DK, Wichterle H
18. Lineage-based identification of cellular states and expression programs.
    Bioinformatics (2012 Jun 15) PMC3371836 free full-text archive
    Hashimoto T, Jaakkola T, Sherwood R, Mazzoni EO, Wichterle H, Gifford D
19. Embryonic stem cell-based mapping of developmental transcriptional programs.
    Nat Methods (2011 Nov 13) PMC3228994 free full-text archive
    Mazzoni EO, Mahony S, Iacovino M, Morrison CA, Mountoufaris G, Closser M, Whyte WA, Young RA, Kyba M, Gifford DK, Wichterle H
20. Feedback from rhodopsin controls rhodopsin exclusion in Drosophila photoreceptors.
    Nature (2011 Oct 9) PMC3208777 free full-text archive
    Vasiliauskas D, Mazzoni EO, Sprecher SG, Brodetskiy K, Johnston RJ Jr, Lidder P, Vogt N, Celik A, Desplan C
21. An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming.
    Cell (2011 Sep 30) PMID: 21924763
    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
22. Wnt signaling specifies and patterns intestinal endoderm.
    Mech Dev (2011 Sep-Dec) PMC3223331 free full-text archive
    Sherwood RI, Maehr R, Mazzoni EO, Melton DA
23. Distinct visual pathways mediate Drosophila larval light avoidance and circadian clock entrainment.
    J Neurosci (2011 Apr 27) PMC3103866 free full-text archive
    Keene AC, Mazzoni EO, Zhen J, Younger MA, Yamaguchi S, Blau J, Desplan C, Sprecher SG
24. Mir-17-3p controls spinal neural progenitor patterning by regulating Olig2/Irx3 cross-repressive loop.
    Neuron (2011 Feb 24) PMC3062262 free full-text archive
    Chen JA, Huang YP, Mazzoni EO, Tan GC, Zavadil J, Wichterle H
25. Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis.
    Genome Biol (2011) PMC3091300 free full-text archive
    Mahony S, Mazzoni EO, McCuine S, Young RA, Wichterle H, Gifford DK
26. Global control of motor neuron topography mediated by the repressive actions of a single hox gene.
    Neuron (2010 Sep 9) PMC2955411 free full-text archive
    Jung H, Lacombe J, Mazzoni EO, Liem KF Jr, Grinstein J, Mahony S, Mukhopadhyay D, Gifford DK, Young RA, Anderson KV, Wichterle H, Dasen JS
27. Functional diversity of ESC-derived motor neuron subtypes revealed through intraspinal transplantation.
    Cell Stem Cell (2010 Sep 3) PMC2933095 free full-text archive
    Peljto M, Dasen JS, Mazzoni EO, Jessell TM, Wichterle H
28. Iroquois complex genes induce co-expression of rhodopsins in Drosophila.
    PLoS Biol (2008 Apr 22) PMC2323304 free full-text archive
    Mazzoni EO, Celik A, Wernet MF, Vasiliauskas D, Johnston RJ, Cook TA, Pichaud F, Desplan C
29. Drosophila CRYPTOCHROME is a circadian transcriptional repressor.
    Curr Biol (2006 Mar 7) PMID: 16527739
    Collins B, Mazzoni EO, Stanewsky R, Blau J
30. Stochastic spineless expression creates the retinal mosaic for colour vision.
    Nature (2006 Mar 9) PMC3826883 free full-text archive
    Wernet MF, Mazzoni EO, Celik A, Duncan DM, Duncan I, Desplan C
31. The growth regulators warts/lats and melted interact in a bistable loop to specify opposite fates in Drosophila R8 photoreceptors.
    Cell (2005 Sep 9) PMID: 16143107
    Mikeladze‑Dvali T, Wernet MF, Pistillo D, Mazzoni EO, Teleman AA, Chen YW, Cohen S, Desplan C
32. 'One receptor' rules in sensory neurons.
    Dev Neurosci (2004) PMID: 15855768
    Mazzoni EO, Desplan C, Celik A
33. Circadian pacemaker neurons transmit and modulate visual information to control a rapid behavioral response.
    Neuron (2005 Jan 20) PMID: 15664180
    Mazzoni EO, Desplan C, Blau J
34. Homothorax switches function of Drosophila photoreceptors from color to polarized light sensors.
    Cell (2003 Oct 31) PMID: 14636555
    Wernet MF, Labhart T, Baumann F, Mazzoni EO, Pichaud F, Desplan C
35. Immortalized mammary epithelial cells overexpressing protein kinase C gamma acquire a malignant phenotype and become tumorigenic in vivo.
    Mol Cancer Res (2003 Aug) PMID: 12939403
    Mazzoni E, Adam A, Bal de Kier Joffe E, Aguirre‑Ghiso JA
36. Nitric oxide synthase, arginase and cyclooxygenase are involved in muscarinic receptor activation in different murine mammary adenocarcinoma cell lines.
    Int J Mol Med (2002 Jun) PMID: 12011984
    Espanol A, Eijan AM, Mazzoni E, Davel L, Jasnis MA, Sacerdote De Lustig E, Sales ME