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Last update 2022-01-06 10:47:35.185

Eric Allemand Splicing regulation in hematopoietic disorders

Course and current status

09/2020 -    Group leader (CRCN-INSERM); Imagine institute (Paris)

Thematic : Splicing regulation in hematopoietic disorders

Head of the multi-thematic team : Pr Olivier Hermine

Director of institute : Pr. Stanislas LYONNET

 

2009 - 09/2020 Project leader (CRCN-INSERM); Pasteur institute (Paris)

Thematic: Coupling of chromatin remodeling and splicing regulation

Director of department : François SCHWEISGUTH 

 

2006 - 12/2008 Young research investigator (CDD - INSERM); Pasteur institute

Thematic: Coupling of chromatin remodeling and splicing regulation

Director of department : Margaret BUCKINGHAM

 

2001 - 09/2006 Postdoctoral fellow; Cold Spring Harbor Laboratory (NY - USA)

Thematic: Splicing regulation by cell signalling pathways 

Director of institute: Bruce W. STILLMAN

 

2001 - 08/2001 Postdoctoral training; IGMM (Montpellier)

Thematic: Identification of new splicing regulators

Director of institute : Philippe JEANTEUR

 

10/1997 - 03/2001 PhD student; IGMM (Montpellier)

Thematic: Identification of new splicing regulators

Director of institute : Philippe JEANTEUR

Scientific summary

The main objective of my research since my PhD has been to understand how splicing regulates the expression of nascent RNAs produced by the RNA polymerase II. RNA splicing was the field in which I did my PhD at the Institute of Molecular Genetics of Montpellier, and my postdoctoral training in Adrian R. Krainer's laboratory at Cold Spring Harbor (New York), a prestigious and leading group in this field. Upon my return to France, I worked on the coupling between chromatin remodeling and alternative splicing in the group of C. Muchardt at the Pasteur Institute (Paris), then I recently joined the group of Pr. Olivier Hermine at Imagine Institute (Paris) to develop translational projects about hematopoietic disorders.

More than 95% of human genes are controlled by alternative splicing, which is one of the main sources of human gene expression diversity. Splicing defects are detected in ~35% of genetic diseases and involved in cell transformation leading to cancers, in particular those resulting from alterations in the differentiation of hematopoietic cells. Among driver genes of myelodysplastic syndrome and mastocytosis, several splicing factors are targeted by pathogenic mutations, and abundant deregulations of splicing were reported in leukemia and lymphoma. To date, the pathological genomic variations are essentially identified by high throughput analysis of Exome or Whole Genome Sequencing (WGS) using short-read technologies. Such approaches have revolutionized the identification of mutations but do not allow an analysis of splicing defects. The development of Third Generation Sequencing (TGS) technologies offers new perspectives to evaluate splicing defects in the context of the disease.

I am currently characterizing, in the multi-thematic team of Pr. Olivier Hermine, splicing dysregulation in T-Cell Acute Lymphoblastic Leukemia (T-ALL). This cancer results from a blockage of lymphocyte differentiation leading to the clonal malignant proliferation of immature lymphoid cells impeding the normal hematopoiesis. Although 90% of patients have remission after the induction phase, the relapse at 5 years is observed in 50% of children, and only 10% of adults survive to this cancer. Previous genetic analyses using Exome or Whole Genome Sequencing (WGS) have listed several genes targeted by somatic mutations and the global transcriptomes of T-ALL patients reveal profound splicing misregulation. Using the TGS technologies we determined splicing defects affecting expression of T-ALL driver genes. This approach is particularly adapted to assess splicing defects since it provides long sequences deciphering the full repertoire of splice variants. Diversity of the transcriptome is largely underestimated in the genetic analysis of patients and our results have established that individuals present dysregulation of specific alternative transcripts although the global level of RNA produced by T-ALL driver genes remains unaffected. We are aiming to identify new pathological markers associated with splicing regulation to develop therapeutic correction tools.


 

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