CONTACT

Mathieu Gabut
Principal investigator

mathieu.gabut@inserm.fr
+33 426 556 745

Cheney A, 4th floor
Centre Leon Berard
28 rue Laennec
69008 LYON
FRANCE
GABUT Mathieu
Chef d'équipe, CR1 Inserm
mathieu.gabut@inserm.fr

Curriculum vitae

DUC Anne-Cécile

Assistante chercheur CLB
AnneCecile.DUC@lyon.unicancer.fr


BERABEZ Nabila
BOURDELAIS Fleur
Bruelle Marion

Etudiante en thèse

Vuillet Marthe
Etudiante en Master 2 Recherche
Bonnet Charlotte

Etudiante en Médecine
Etudiante en Master 2 Recerche

Voir les objectifs et projets Voir les publications
Collaborations

- Didier Auboeuf                                                                           
  Cancer Research Centre of Lyon
  [Auboeuf lab web site]

- Pr. Jérome Honnorat                                                                      
  Neuroscience Research Centre of Lyon
  [Honnorat lab web site]

- Alexandra Benchoua
  iSTEM
  [Benchoua lab web site]

- Pr. Benjamin Blencowe                          
  Donnelly Centre, University of Toronto
  [blencowe lab web site]

Founding

ATIP-AVENIR Program 2014-2017
Foundation for Cancer Research
Inserm
Marie Curie Actions
National Cancer Institute
La ligue: Rhône Committee

Award

2012 Lap-Chee Tsui Publication Award from the Canadian Institute for Health Research (CIHR).

OBJECTIVES

Alternative splicing is a crucial step of messenger RNA maturation which plays a key role in regulating gene expression as well as expanding the proteome and transcriptome diversity in a cell specific manner. We recently revealed a central role for alternative splicing in the regulation of the core pluripotency circuitry and fate decisions of embryonic stem cells.

The major focus of the team is to combine molecular and transcriptomic approaches in order to identify mechanisms that coordinate alternative splicing regulation in embryonic stem cells and in a model of cancer stem cells responsible for the most prevalent primary brain tumors: the glioblastomas.

PROJECT

Our main focus is to identify factors and signalling pathways which control the functional diversity of stem cell's transcriptomes as well as the expression of gene networks underlying stem cell fate. More precisely, we are investigating the role and regulation of alternative splicing for the control of stem cell identity and fate.

Scientific context :

Alternative splicing is the mechanism by which exons from the precursor messenger RNAs are differentially included to allow the synthesis, from a single gene, of multiple mRNA isoforms with variable coding capacities. Recent genome-wide studies have revealed that alternative splicing acts on transcripts from at least 95% of human multi-exon genes and plays a prevalent role in expanding the proteome and transcriptome complexity. Alternative splicing is regulated in a cell-specific manner to control the expression of gene networks underlying many cellular processes such as cell differentiation and tissue development.

    Recent studies from our team and other labs (Gabut et al, Cell, 2011) revealed that an increasing number of splicing events are regulated during embryonic stem cell (ESC) differentiation and during the reprogramming of somatic cells in induced pluripotent stem cells (iPSC) (Han et al, Nature, 2013). These events and exons define splicing programs, conceptually similar to transcription programs, which functions remain to be established in embryonic and adult stem cells.

    We identified a highly conserved AS switch that encodes specific amino acid changes in the DNA binding domain of the human transcription factor FOXP1, and modifies its DNA-binding specificity. Inclusion of the switch (red) exon specifically in ESC stimulates the expression of key pluripotency genes such as OCT4 and NANOG while repressing the expression of differentiation genes, whereas skipping of this exon is required for ESC differentiation. This splicing event is conserved in mouse ESC, promotes the maintenance of pluripotency, and is critical for efficient reprogramming of somatic cells to iPSC.

    These results have paradigm shifting implications in the way we think about the regulation of the core pluripotency circuitry. Indeed, alternative splicing can now be placed upstream of this core transcriptional network to play a central role in shaping the landscape of gene regulation that controls the physiology and fate of pluripotent stem cells.

Research objectives :

  In this context, our focus will be to further characterize the importance of alternative splicing for the regulation of the molecular pathways controlling stem cell identity and fate. We are addressing this question in the context of both normal stem cells (ESC) as well as in a model of pathological stem cells, cancer stem cells responsible for the most prevalent primary brain tumours: the glioblastomas.

In particular, by combining multidisciplinary approaches, we are interested in:

1- Defining the function of splicing programs expressed in ESC for the maintenance of their pluripotency
    and self-renewal properties.

2- identifying the factors and signalling pathways which coordinate ESC splicing programs.

3- investigating the role of alternative splicing regulation for the survival and tumorigenic capacities of
    glioblastoma stem cells

 

PUBLICATIONS

2013

Han H, Irimia M, Ross PJ, Sung HK, Alipanahi B, David L, Golipour A, Gabut M, Michael IP, Nachman EN, Wang E, Trcka D, Thompson T, O'Hanlon D, Slobodeniuc V, Barbosa-Morais NL, Burge CB, Moffat J, Frey BJ, Nagy A, Ellis J, Wrana JL, Blencowe BJ. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature. 2013. 498(7453):241-5. [PMID: 23739326

2012

Gabut M. Pluripotence des cellules souches: quand l’épissage alternatif s’en mêle. Médecine Sciences. 2012. 28(4):372-4. [PMID: 22549864]

2011

Gabut M, Samavarchi-Tehrani P, Wang X, Slobodeniuc V, O’Hanlon D, et al. An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming. Cell2011. 17(1):132-146 [PMID: 21924763]

2009

Calarco JA, Superina S, O'Hanlon D, Gabut M, Raj B, et al. Regulation of vertebrate nervous system alternative splicing and development by an SR-related protein. Cell2009. 138(5):898-910. [PMID: 19737518].

2008

Gabut M, Chaudhry S, Blencowe BJ. The splicing regulatory machinery. Cell2008. 133(1):192.e1. [PMID: 18394998]. 

2007

Gabut M, Dejardin J, Tazi J, Soret J. The SR family proteins B52 and dASF/SF2 modulate development of the Drosophila visual system by regulating specific RNA targets. Mol Cell Biol2007. (8):3087-97. [PMID: 17283056].

2006

Soret J, Gabut M, Tazi J. SR proteins as potential targets for therapy. Prog Mol Subcell Biol2006. 4:65-87. [PMID: 17076265].

2005

Soret J, Bakkour N, Maire S, Durand S, Zekri L, Gabut M, et al. Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors. PNAS2005. 102(24):8764-9. [PMID: 15939885].

Gabut M, Miné M, Marsac C, Brivet M, Tazi J, Soret J. The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis. Mol Cell Biol2005. (8):3286-94. [PMID: 15798212].

2003

Soret J*, Gabut M*, Dupon C, Kohlhagen G, Stévenin J, et al. Altered serine/arginine-rich protein phosphorylation and exonic enhancer-dependent splicing in Mammalian cells lacking topoisomerase I. Cancer Res2003. 63(23):8203-11. [PMID: 14678976]. (* co-first authors)

Bantignies F, Grimaud C, Lavrov S, Gabut M, Cavalli G. Inheritance of Polycomb-dependent chromosomal interactions in Drosophila. Genes Dev2003. 17(19):2406-20. [PMID: 14522946].

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