Research projects

During their transformation, cancer cells undergo a process of dedifferentiation, with gene activation associated with reduced chromatin compaction. This process correlates with epigenetic modifications, among others, of the trimethylated lysine-4 of histone H3 (H3K4me3).  This modification also occurs during differentiation of stem cells. Thus, the different hematopoietic cell lineages generated from hematopoietic stem cells require the gradual silencing of specific genes and the regulation of the expression of lineage-specific transcription factors.

DIDO3 is a protein that acts as a "reader" of the epigenetic mark H3K4me3 and participates in the process of differentiation of stem cells. Its deficiency is correlated with transcriptional alterations and an increased incidence of myelodysplasia, myeloproliferation, melanoma and infertility.

In this project we have generated, in the murine model, a Dido mutant, specifically of the Dido3 isoform, by means of a conditional deficiency in hematopoietic cells, to study the impact on the differentiation of B cells. Mice lacking Dido3 show a virtual absence of B-lymphocytes, as well as a decrease in the accessibility of DNA in the chromatin of hematopoietic precursors. The identified bone marrow defects extend to the periphery in the form of severe lymphopenia, with a 95% decrease in the number of B cells.

Mutant B cell precursors show low levels of transcription of the factors determining B lineage, as well as an absence of silencing of stemness genes. As a consequence, these precursors are unable to express differentiation markers and, consequently, to generate mature cells. The analysis of chromatin structure and transcriptional activity carried out in these precursors by means of ChIP-Seq, ATAC-Seq and RNA-Seq assays indicate that the observed defect is compatible with the lack of activity of the Polycomb 2 Repressor Complex (PRC2), regulated by DIDO3 and whose function is fundamental for the identification of active genes during the early stages of differentiation, among them the genes that encode for the heavy chain of immunoglobulin. In conclusion, DIDO3 stands out as an epigenetic regulator of the differentiation of the lymphoid B series.