Abstract
High mobility group A (HMGA) proteins are chromatinic proteins that do not have transcriptional activity per se, however, by interacting with the transcription machinery, they regulate, negatively or positively, the expression of several genes. We searched for genes regulated by HMGA1 proteins using microarray analysis in embryonic stem (ES) cells bearing one or two disrupted hmga1 alleles. We identified 87 transcripts increased and 163 transcripts decreased of at least 4-fold in hmga1-/- ES cells. For some of them, a HMGA1-dose dependency was observed, because an intermediate level was observed in the heterozygous ES cells. When the expression analysis of these genes was extended to embryonic fibroblasts and adult tissues such as heart, spleen, and liver from hmga1-knockout mice, contrasting results were obtained. In fact, aside some genes showing the same HMGA1 regulation observed in ES cells, there were some genes that did not modify their expression, and others showing a HMGA1-mediated regulation but in an opposite direction. These results clearly indicate that HMGA1-mediated gene regulation depends on the cellular context. Finally for a couple of analyzed HMGA1-regulated genes, electrophoretic mobility shift assay and chromatin immunoprecipitation revealed a direct binding of HMGA1 proteins to their promoters, suggesting a HMGA1-direct regulation of their expression.
Highlights
The high mobility group A (HMGA) protein family includes HMGA1a and HMGA1b, which are encoded by hmga1 through alternative splicing [1] and the closely related HMGA2 protein [2]
Their DNA-binding domain is located in the NH2-terminal region of the protein and contains three short basic repeats, the so-called “AThooks.” The mammalian HMGA proteins have long been known to play key roles in chromatin architecture and gene control by serving as generalized chromatin effectors, either enhancing or suppressing the ability of more usual transcriptional activators and repressors to act within the confines of chromatinized DNA [3, 4]
We screened an array in which 13,059 transcripts were represented, and we identified 87 transcripts that increased and 163 transcripts that decreased with a Ն4-fold change in hmga1Ϫ/Ϫ embryonic stem (ES) cells with respect to the wild-type ES cells
Summary
The high mobility group A (HMGA) protein family includes HMGA1a and HMGA1b, which are encoded by hmga1 through alternative splicing [1] and the closely related HMGA2 protein [2]. Re-expression of the hmga1 gene in hmga1Ϫ/Ϫ ES cells restores the wild-type phenotype [9]. These results indicate that drastic changes occur in the transcriptional activity of the hmga1Ϫ/Ϫ cells, and presumably they depend on the modification of the expression of HMGA1-regulated genes.
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