Splicing regulation in 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.

In the team of Prof. Olivier Hermine, I am characterizing splicing dysregulation in hematological disorders by using the Third Generation Sequencing technologies (TGS). This methodology is well adapted to analyse alternative splicing since it provides long sequences allowing to decipher the full repertoire of splice variants. Diversity of the transcriptome is largely underestimated in the genetic analysis of patients. We are aiming to identify new pathological markers associated with splicing regulation and study their functional consequences in order to develop correction tools.

Selected publications:

-     Analysis of splicing regulation by Third-Generation Sequencing. Eric allemand  and Fabrice Ango. MiMB, 2021 (in press, release in July)

- Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity. Dos Reis R, Kornobis E, Pereira A, Tores F, Carrasco J, Gautier C, Jahannault-Talignani C, Nitschké P, Muchardt C, Schlosser A, Maric HM, Ango F, Allemand E. Nature Communications, 2022 Jun 18;13(1):3507. PMID: 35717442

-     A Broad Set of Chromatin Factors Influences Splicing. Eric Allemand, Michael P Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R Krainer, Christian Muchardt. PLoS Genet, 2016 Sep 23;12(9):e1006318. PMID: 27662573

-     Alternative splicing regulates the expression of G9A and SUV39H2 methyltransferases, and dramatically changes SUV39H2 functions. Oriane Mauger, Roscoe Klinck, Benoit Chabot, Christian Muchardt, Eric Batsché, Eric Allemand. Nucleic Acids Res. 2015 Feb 18;43(3):1869-82. PMID: 25605796

-     Alternative splicing regulation by interaction of phosphatase PP2Cgamma with nucleic acid-binding protein YB-1. Eric Allemand, Michelle L Hastings, Michael V Murray, Michael P Myers, Adrian R Krainer. Nat Struct Mol Biol. 2007 Jul;14(7):630-8. PMID: 17572683