RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription.

RUNX1 (AML1) is a gene that is frequently disrupted by chromosomal translocations in acute leukemia. Like its Drosophila homolog Runt, RUNX1 both activates and represses transcription. Both Runt and RUNX1 are required for gene silencing during development and a central domain of RUNX1, termed repression domain 2 (RD2), was defined as being required for transcriptional repression and for the silencing of CD4 during T-cell maturation in thymic organ cultures. Although transcriptional co-repressors are known to contact other repression domains in RUNX1, the factors that bind to RD2 had not been defined. Therefore, we tested whether RD2 contacts histone-modifying enzymes that may mediate both repression and gene silencing. We found that RD2 contacts SUV39H1, a histone methyltransferase, via two motifs and that endogenous Suv39h1 associates with a Runx1-regulated repression element in murine erythroleukemia cells. In addition, one of these SUV39H1-binding motifs is also sufficient for binding to histone deacetylases 1 and 3, and both of these domains are required for full RUNX1-mediated transcriptional repression. The association between RUNX1, histone deacetylases and SUV39H1 provides a molecular mechanism for repression and possibly gene silencing mediated by RUNX1.

[Molecular characterization of thalassemias in the Valencia community and its relationship with the hematological phenotype]. / Caracterización molecular de las talasemias en la Comunidad Valenciana y su relación con el fenotipo hematológico.

PURPOSE: The aim of the study is to present the first results of molecular characterization of thalassaemias in Valencian Community and their relationship with the haematological parameters. PATIENTS AND METHODS: The study includes 87 thalassemic patients: 30 alpha-thalassaemias, 40 beta-thalassaemias and 17 delta beta-thalassaemias. The molecular alterations were studied in white cell blood DNA, either following different PCR methods or by testing the digestion of the amplified PCR products with selective restriction enzymes. RESULTS: The molecular characterization of beta-thalassaemias was achieved in 94% of the subjects, being the transition C-->T in CD-39 the most frequent (44%) of the mutations studied. 94% of the delta beta-thalassaemias studied corresponded to the delta beta-Spanish type. All the alpha thalassaemias characterized (64%) corresponded to the -alpha 3.7 deletion. The reamining 36% were negative for the alpha 0 deletions --MED, --20.5, or the non deletional mutations Hph I and NocI. DISCUSSION: In the Valencian Community, like what has been described for the beta-thalassaemias in other Mediterranean regions of Spain (Barcelona, Granada and Mallorca), a high incidence in C-->T transition in CD-39 was observed, in contrast with central and south-western regions of Spain, where the G-->A IVS-I-1 is the most frequent mutation. Our study supports that the IVS-I-6 mutations is the one with lower repercussions on the haematological parameters. Our study confirms the Spanish type of delta beta-thalassaemia as the most frequent in the Valencian Community, and that the 3.7 kb alpha deletion is the most frequent mutation for the alpha-thalassaemia, although alpha thalassaemia is also the poorly characterized form of thalassaemia.