Stem Cell Gene SALL4 Suppresses Transcription through Recruitment of DNA Methyltransferases

Abstract

Background: SALL4 is a critical transcription factor for stem cell character maintenance. Results: SALL4 protein interacts with different DNA methyltransferases and associates with enzymatic activities. Overexpression of SALL4 induced increased DNA methylation in promoter regions of silenced genes. Conclusion: SALL4 may form a large complex with epigenetic modifiers in suppressing gene expression. Significance: A novel mechanism is provided by which stem gene SALL4 negatively regulates target genes.

Histone Lysine-specific Demethylase 1 (LSD1) Protein Is Involved in Sal-like Protein 4 (SALL4)-mediated Transcriptional Repression in Hematopoietic Stem Cells

“…A Gateway reaction in the attL and attR sites was carried out to subclone the cDNA into the lentiviral expression vector pDEST-CMVFG12 (11). Plasmids expressing SALL4 isoforms and shortened mutants were described elsewhere (13). The pEBF1-Luc reporter was kindly provided by Dr. Rudolf Grosschedl (23).…”

“…Transfection of plasmids into cultured cells was performed using Lipofectamine 2000 (Invitrogen) according to the manufacturer's recommendations. Luciferase assays were performed as described previously (13). PCPA was purchased from Sigma.…”

“…Co-immunoprecipitation and Western Blotting-Protein interaction assays were conducted as described (13). LSD1 antibody was purchased from Cell Signaling.…”

“…We have sought to examine the potential transcriptional and/or epigenetic mechanisms underlining the observed SALL4 effects on BM progenitor cells. To this end, we and others have reported that SALL4 can silence lineage differentiation genes and modulate cell proliferation by recruiting epigenetic regulators, including DNA methyltransferases (DNMT1, 3A, 3B, 3L) and histone deacetylases (HDAC1 and HDAC2), to target genes (13)(14)(15). In addition, SALL4-mediated activation of Bmi-1, another important hematopoietic stem cell gene, involves methylation of lysine 4 of histone H3 * This work was supported, in whole or in part, by National Institutes of Health Grants R01HL087948 (to Y. M.) and R01 HL090589 (to S. H.).…”

Targeting the epigenome in malignant pleural mesothelioma

“…Given their direct roles in silencing tumor suppressor genes and maintaining pluripotency (114,115) The lack of efficacy of DNA hypomethyating agents in solid tumors to date may be related to the fact that these agents have been dosed to maximum tolerated levels resulting in myelosuppression rather than administered chronically at lower doses to achieve pharmacodynamic effects without systemic toxicities. Data from our phase I decitabine (DAC) trial clearly demonstrate that chronic exposures are required to achieve maximal gene induction effects in cancer tissues (117).…”