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Molecular mechanisms of transcriptional regulation of lymphocyte development by the E2A splice variants E12 and E47

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Molecular events governing lymphocyte development

Lymphocytes are key effector cells of our immune system. Understanding the molecular mechanisms that drive their development could help understand many immune-related diseases.

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During development, cell fate is governed through the carefully controlled activity of various transcription factors. These regulate gene expression and dictate differentiation of mature cells from progenitors. During B and T lymphocyte development, the E2A gene seems to play an instrumental role through its alternatively spliced transcription factors E12 and E47. Accumulating evidence indicates that these two variants act at different stages of B cell differentiation and maturation, including immunoglobulin gene rearrangement. The scope of the EU-funded SPLICE (Molecular mechanisms of transcriptional regulation of lymphocyte development by the E2A splice variants E12 and E47) project was to identify the signalling events that control transcription and splicing of the E2A gene and define the interacting partners of the two variants. In this context, scientists used mice lacking either the E12 or the E47 proteins and obtained B cell populations that reflected the different maturation stages. Genomic analysis through chromatin immunoprecipitation and deep sequencing unveiled that the E2A proteins affected the histone modifications on the immunoglobulin locus. Epigenetic modification of the immunoglobulin locus is central for its transcription and rearrangement. Mass spectrometry analysis of E47 protein complexes identified various transcriptional cofactors (CoREST1, Dnmt1), which interacted with E47. Additionally, researchers investigated E2A splicing and identified specific regulators, thereby shedding light onto the emergence of the E2A variants. Overall, the results of the SPLICE project highlighted for the first time the need for two highly similar proteins during B cell development. The acquired knowledge could be used for understanding the transcriptional regulation of other genes.


Lymphocyte, transcription factors, E2A gene, immunoglobulin

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