Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stem cell protein SALL4 plays a vital role in maintaining stem cell identity and governing stem cell self-renewal through transcriptional repression. To explore SALL4-mediated mechanisms involved in transcriptional repression, we investigated DNA modifications underlying its regulatory activities. By a luciferase activity assay, we found that both histone deacetylase inhibitor valproic acid (VPA) and DNA methylation inhibitor 5-azacytidine (5-azaC) specifically reversed the repression effect of SALL4 on its own as well as other Sal gene promoter activities. Cotreatment of VPA with 5-azaC in cells almost completely blocked this repression effect. Further co-immunoprecipitation assay and enzyme activity analysis demonstrated that SALL4 protein directly interacted with different DNA methyltransferases (DNMTs) and purified DNMT enzymatic activities from nuclear extracts. In addition, SALL4 isoforms co-occupied the same regions of its own promoter as DNMT corepressors, and ectopic overexpression of SALL4 led to increased CpG island promoter methylation of silenced genes in various cell types. These included primary hematopoietic stem/progenitor cells, fibroblasts, and NB4 leukemic cells. In NB4 cells, treatment of cells with 5-azaC also caused decreased amounts of methylated alleles of SALL4 and PTEN and dramatically increased their mRNA expression. Our studies identify a new mechanism by which SALL4 represses gene expression through interaction with DNMTs. Furthermore, DNMTs and histone deacetylase repressors synergistically contribute to the regulatory effects of SALL4. These findings provide new insights into stem cell self-renewal mediated by SALL4 via epigenetic machinery.
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PMID:Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases. 2212 85

Hematopoietic stem cells (HSCs) are widely used in transplantation therapy to treat a variety of blood diseases. The success of hematopoietic recovery is of high importance and closely related to the patient's morbidity and mortality after Hematopoietic stem cell transplantation (HSCT). We have previously shown that SALL4 is a potent stimulator for the expansion of human hematopoietic stem/progenitor cells in vitro. In these studies, we demonstrated that systemic administration with TAT-SALL4B resulted in expediting auto-reconstitution and inducing a 30-fold expansion of endogenous HSCs/HPCs in mice exposed to a high dose of irradiation. Most importantly, TAT-SALL4B treatment markedly prevented death in mice receiving lethal irradiation. Our studies also showed that TAT-SALL4B treatment was able to enhance both the short-term and long-term engraftment of human cord blood (CB) cells in NOD/SCID mice and the mechanism was likely related to the in vivo expansion of donor cells in a recipient. This robust expansion was required for the association of SALL4B with DNA methyltransferase complex, an epigenetic regulator critical in maintaining HSC pools and in normal lineage progression. Our results may provide a useful strategy to enhance hematopoietic recovery and reconstitution in cord blood transplantation with a recombinant TAT-SALL4B fusion protein.
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PMID:Enhancing bone marrow regeneration by SALL4 protein. 2428 61