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Lab presentation

During animal development, the differentiation of cells, tissues and organs is tightly regulated through specific gene expression programs. Our group is particularly interested in studying the transcriptional and cell signaling mechanisms responsible for this control.

Using Drosophila as a model system, we have been dissecting the activities of repressor and co-repressor factors, as well as the responses induced by receptor tyrosine kinase (RTK) pathways during pattern formation and differentiation. One emerging theme has been the identification of the Capicua transcriptional repressor as a general sensor targeted by multiple RTK-initiated signals. Because the molecules and pathways that we study are conserved in evolution, our results have direct implications for human biology and disease.

To find out more about our lab, please visit also my ICREA website

Projects

Molecular analysis of Capicua, an RTK signaling sensor. The RTK-Ras-Erk signaling pathway regulates a myriad of cellular and developmental processes and is the most frequently mutated signaling pathway in human cancer. Using Drosophila as a model system, we are studying how RTK signaling directs specific gene responses in the nucleus. We have found that the HMG-box protein Capicua (Cic) is an important mediator of such responses. Cic acts antagonistically to RTK signaling in a relatively simple switch: in the absence of signaling, Cic represses RTK-induced targets, whereas RTK activation causes Cic downregulation and derepression of its targets. Importantly, Cic is similarly regulated by RTK signaling in mammals and has been implicated in human neurodegeneration and in various forms of cancer, where it behaves as a tumor suppressor. Recently, we have found that Cic employs a new mode of DNA binding that distinguishes it from other HMG-box factors and explains its mutation patterns in cancer

Transcriptional regulation in Drosophila embryonic patterning. Precise spatio-temporal control of gene expression is at the heart of animal development. We are interested in the mechanisms and factors that mediate this control during Drosophila development. In particular, we have studied several tiers of transcriptional regulation for the establishment and patterning of the Drosophila anteroposterior and dorsoventral embryonic axes, including a mechanism in which binding of Cic to distinct DNA sites controls the simultaneous spatial subdivision of both axes.

Function and specificity of transcriptional corepressors. We also have a long-term interest in eukaryotic transcriptional repression and corepressors. Corepressors usually serve as a link between DNA binding transcriptional repressors and the actual downstream mechanisms leading to transcriptional repression, such as chromatin compaction. However, what dictates the specificity of corepressors –their involvement in one particular regulatory context or another– is not well understood in most cases. We are addressing this question by studying the activities of two conserved corepressors, Groucho/TLE and Atrophin.

 

Lab people

Principal investigator

Gerardo Jiménez is an ICREA Research Professor. He graduated in Biology from the University of Barcelona and obtained his PhD in 1993 for work carried out in the laboratories of Tariq Enver and Mel Greaves at the Institute of Cancer Research in London.

He then worked as a postdoctoral fellow in the laboratory of David Ish-Horowicz at Cancer Research UK, in Oxford and in London. Since then, his research has centered on the molecular mechanisms and pathways that regulate gene expression during animal development. He is head of the Gene expression and signaling laboratory since 2002.

Past students

Marta Forés

Postdoctoral Researcher

Aikaterini Papagianni

PhD Student

María José Andreu

PhD Student

Leiore Ajuría

PhD Student

Selected publications

Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

Papagianni A, Forés M, Shao W, He S, Koenecke N, Andreu MJ, Samper N, Paroush Z, González-Crespo S, Zeitlinger J, Jiménez G.

Proc Natl Acad Sci USA 2018, 115, 1807-1812.

Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma

Simón-Carrasco L, Graña O, Salmón M, Jacob HKC, Gutierrez A, Jiménez G, Drosten M, Barbacid M.

Genes Dev 2017, 31, 1456-1468.

A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer

Forés M, Simón-Carrasco L, Ajuria L, Samper N, González-Crespo S, Drosten M, Barbacid M, Jiménez G.

PLOS Genet 2017, 11, e1006622.

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua

Yang L, Paul S, Trieu KG, Dent LG, Froldi F, Forés M, Webster K, Siegfried KR, Kondo S, Harvey K, Cheng L, Jiménez G, Shvartsman SY, Veraksa A

Proc Natl Acad Sci USA 2017, 113, 10583-10588.

EGFR/Ras signaling controls Drosophila intestinal stem cell proliferation via Capicua-regulated genes

Jin Y, Ha N, Forés M, Xiang J, Glaßër C, Maldera J, Jiménez G, Edgar BA.

PLOS Genet 2015, 11, e1005634.

Origins of context-dependent gene repression by Capicua

Forés M, Ajuria L, Samper N, Astigarraga S, Nieva C, Grossman R, González-Crespo S, Paroush Z, Jiménez G.

PLOS Genet 2015, 11, e1004902.

Kinetics of gene derepression by ERK signaling

Lim B, Samper N, Lu H, Rushlow C, Jiménez* G, Shvartsman* SY.

Proc Natl Acad Sci USA 2013, 110, 10330-10335.

Mirror represses pipe expression in follicle cells to initiate dorsoventral axis formation in Drosophila

Andreu MJ, González-Pérez E, Ajuria L, Samper N, González-Crespo S, Campuzano S, Jiménez G. Development 2012, 139, 1110-1114.

The Capicua repressor – a general sensor of RTK signaling in development and disease

Jiménez G, Shvartsman S, Paroush Z.

J Cell Sci 2012, 125, 1383-1391.

Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila

Ajuria L, Nieva C, Winkler C, Kuo D, Samper N, Andreu MJ, Helman A, González-Crespo S, Paroush Z, Courey AJ, Jiménez G.

Development 2011, 138, 915-924.

Phosphorylation of Groucho mediates RTK feddback inhibition and prolonged pathway target gene expression

Helman A, Cinnamon E, Mezuman S, Hayouka Z, von Ohlen T, Orian, A, Jiménez G., Paroush Z. Curr Biol 2011, 21, 1102-1110.

Substrate-dependent control of MAPK phosphorylation in vivo

Kim Y, Paroush Z, Nairz K, Hafen E, Jiménez* G, Shvartsman* SY.

Mol Syst Biol 2011, 7, article number 467.

A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling

Astigarraga S, Grossman R, Díaz-Delfín J, Caelles C, Paroush Z, Jiménez G.

EMBO J 2007, 26, 668-677.

The Tailless nuclear receptor acts as a dedicated repressor in the early Drosophila embryo

Morán E, Jiménez G.

Mol Cell Biol 2006, 26, 3446-3454.

All publications

Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

Papagianni A, Forés M, Shao W, He S, Koenecke N, Andreu MJ, Samper N, Paroush Z, González-Crespo S, Zeitlinger J, Jiménez G.

Proc Natl Acad Sci USA 2018, 115, 1807-1812.

The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer

Simón-Carrasco L, Jiménez G, Barbacid M, Drosten M.

Cell Cycle 2018, 17, 702-711.

Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma

Simón-Carrasco L, Graña O, Salmón M, Jacob HKC, Gutierrez A, Jiménez G, Drosten M, Barbacid M.

Genes Dev 2017, 31, 1456-1468.

A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer

Forés M, Simón-Carrasco L, Ajuria L, Samper N, González-Crespo S, Drosten M, Barbacid M, Jiménez G.

PLOS Genet 2017, 11, e1006622.

ERK Signaling: Methods and Protocols

Jiménez G (ed)

Methods in Molecular Biology, Springer, New York, 2017.

Using CRISPR-Cas9 to study ERK signaling in Drosophila

Forés M., Papagianni A, Rodríguez-Muñoz L, Jiménez G.

Methods Mol Biol 2017, 1487, 353-365.

Minibrain and Wings apart control organ growth and tissue patterning through downregulation of Capicua

Yang L, Sayantanee P, Trieu KG, Dent LG, Froldi F, Forés M, Webster K, Siegfried KR, Kondo S, Harvey K, Cheng LY, Jiménez G, Shvartsman SY, Veraksa A.

Proc Natl Acad Sci USA 2016, 113, 10583-10588.

A systematic ensemble approach to thermodynamic modeling of gene expression from sequence data

Samee MAH, Lim B, Samper N, Lu H, Rushlow CA, Jiménez G, Shvartsman SY, Sinha S.

Cell Syst 2015, 1, 396-407.

EGFR/Ras signaling controls Drosophila intestinal stem cell proliferation via Capicua-regulated genes

Jin Y, Ha N, Forés M, Xiang J, Gläβer C, Maldera J, Jiménez G, Edgar BA.

PLOS Genet 2015, 11, e1005634.

Origins of context-dependent gene repression by Capicua

Forés M, Ajuria L, Samper N, Astigarraga S, Nieva C, Grossman R, González-Crespo S, Paroush Z, Jiménez G.

PLOS Genet 2015, 11, e1004902.

Kinetics of gene derepression by ERK signaling

Lim B, Samper N, Lu H, Rushlow C, Jiménez* G, Shvartsman* SY.

Proc Natl Acad Sci USA 2013, 110, 10330-10335.

EGFR-dependent downregulation of Capicua and the establishment of Drosophila dorsoventral polarity

Andreu MJ, Ajuria L, Samper N, González-Pérez E, Campuzano S, González-Crespo S, Jiménez G.

Fly (Austin) 2012, 6, 234-239.

Mirror represses pipe expression in follicle cells to initiate dorsoventral axis formation in Drosophila

Andreu MJ, González-Pérez E, Ajuria L, Samper N, González-Crespo S, Campuzano S, Jiménez G.

Development 2012, 139, 1110-1114.

The Capicua repressor a general sensor of RTK signaling in development and disease

Jiménez G, Shvartsman SY, Paroush Z.

J Cell Sci 2012, 125, 1383-1391.

RTK signaling modulates the Dorsal gradient

Helman A, Lim B, Andreu MJ, Kim Y, Shestkin T, Lu H, Jiménez G, Shvartsman SY, Paroush Z.

Development 2012, 139, 3032-3039.

Phosphorylation of Groucho mediates RTK feedback inhibition and prolonged pathway target gene expression

Helman A, Cinnamon E, Mezuman S, Hayouka Z, Von Ohlen T, Orian A, Jiménez G, Paroush Z.

Curr Biol 2011, 21, 1102-1110.

Gene regulation by MAPK substrate competition

Kim Y, Andreu MJ, Lim B, Chung K, Terayama M, Jiménez G, Berg CA, Lu H, Shvartsman SY.

Dev Cell 2011, 20, 880-887.

Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila

Ajuria L, Nieva C, Winkler C, Kuo D, Samper N, Andreu MJ, Helman A, González-Crespo S, Paroush Z, Courey AJ, Jiménez, G.

Development 2011, 138, 915-924.

Substrate- dependent control of MAPK phosphorylation in vivo

Kim Y, Paroush Z, Nairz K, Hafen E, Jiménez* G, Shvartsman* SY.

Mol Syst Biol 2011, 7, article number 467.

MAPK substrate competition integrates patterning signals in the Drosophila embryo

Kim Y, Coppey M, Grossman R, Ajuria L, Jiménez G, Paroush Z and Shvartsman SY.

Curr Biol 2010, 20, 446-451.

Multiple RTK pathways downregulate Groucho-mediated repression in Drosophila embryogenesis

Cinnamon E, Helman A, Ben-Haroush Schyr R, Orian A, Jiménez G, Paroush Z.

Development 2008, 135, 829-837.

A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling

Astigarraga S, Grossman R, Díaz-Delfín J, Caelles C, Paroush Z, Jiménez G.

EMBO J 2007, 26, 668-677.

The Tailless nuclear receptor acts as a dedicated repressor in the early Drosophila embryo

Morán E, Jiménez G.

Mol Cell Biol 2006, 26, 3446-3454.

The ε-subunit of ATP synthase is required for normal spindle orientation during the Drosophila embryonic divisions

Kidd T, Abu-Shumays R, Katzen A, Sisson JC, Jiménez G, Pinchin S, Sullivan W, Ish-Horowicz D.

Genetics 2005, 170, 697-708.

Capicua integrates input from two maternal systems in Drosophila terminal patterning

Cinnamon E, Gur-Wahnon D, Helman A, St Johnston D, Jiménez G, Paroush Z.

EMBO J 2004, 23, 4571-4582.

EGFR signalling inhibits Capicua-dependent repression during specification of Drosophila wing veins

Roch F, Jiménez G, Casanova J.

Development 2002, 129, 993-1002.

Cell surface proteins Nasrat and Polehole stabilize the Torso-like extracellular determinant in Drosophila oogenesis

Jiménez G, González-Reyes A, Casanova J.

Genes Dev 2002, 16, 913-918.

Relief of gene repression by Torso RTK signaling: role of capicua in Drosophila terminal and dorsoventral patterning

Jiménez G, Guichet A, Ephrussi A, Casanova J.

Genes Dev 2000, 14, 224-231.

Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family

Eberhard D, Jiménez G, Heavy B, Busslinger M.

EMBO J 2000, 19, 2292-2303.

Huckebein repressor activity in Drosophila terminal patterning is mediated by Groucho

Goldstein RE, Jiménez G, Cook O, Gur D, Paroush Z.

Development 1999, 126, 3747-3755.

A conserved motif in Goosecoid mediates Groucho-dependent repression in Drosophila embryos

Jiménez G, Verrijzer CP, Ish-Horowicz D.

Mol Cell Biol 1999, 19, 2080-2087.

Groucho acts as a corepressor for a subset of negative regulators, including Hairy and Engrailed

Jiménez G, Paroush Z, Ish-Horowicz D.

Genes Dev 1997, 11, 3072-3082.

A chimeric Enhancer-of-split transcriptional activator drives neural development and achaete-scute expression

Jiménez G, Ish-Horowicz D.

Mol Cell Biol 1997, 17, 4355-4362.

In vivo interactions of the Drosophila Hairy and Runt transcriptional repressors with target promoters

Jiménez G, Pinchin SM, Ish-Horowicz D.

EMBO J 1996, 15, 7088-7098.

Analysis of the developmental and transcriptional potentiation functions of 5’HS2 of the murine β-globin locus control region in transgenic mice

Enver T, Li Q, Gale KB, Hu M, May GE, Karlinsey JE, Jiménez G, Papayannopoulou T, Costantini F.

Dev Biol 1994, 165, 574-584.

Multiple changes in chromatin structure precede the transcriptional activation of the human growth hormone locus in placental cells

Jiménez G, Ford AM, Enver T, Boronat A.

Mol Cell Endocrinol 1993, 96, 53-60.

Activation of the β-globin locus control region precedes commitment to the erythroid lineage

Jiménez G, Griffiths S, Ford AM, Greaves MF, Enver T.

Proc Natl Acad Sci USA 1992, 89, 10618-10622.

The mouse β-globin locus control region: hypersensitive sites 3 and 4

Jiménez G, Gale KB, Enver T.

Nucleic Acids Res 1992, 20, 5797-5803.

SphI RFLP at the human growth hormone gene cluster

Jiménez G, Ford AM, Boronat A.

Nucleic Acids Res 1992, 20, 1169.

Project funding

 

2018-2020

Transcriptional interpretation of RTK signaling

Funded by the Spanish Government (Ref. BFU2017-87244-P)

Role: PI

2018-2020

Chromatin and gene expression

Funded by the Catalan Government (Ref. 2017 SGR 475)

Role: Co-PI

2015-2017

Transcriptional regulation by RTK signaling

Funded by the Spanish Government (Ref. BFU2014-52863-P)

Role: PI

2013-2016

Molecular analysis of Capicua, a novel tumor suppressor involved in RTK signaling and transcriptional repression

Funded by the Marató de TV3 (Ref. 20131730)

Role: Co-PI and Coordinator

2003-2014

Four consecutive projects funded by the Spanish Government

Role: PI

Vacancies/Jobs

We welcome enquiries from prospective undergraduate students, PhD students and postdoctoral researchers. Please contact us by e-mail (gjcbmc@ibmb.csic.es).

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