Identification of the Genes Up- and Down-Regulated by the High Mobility Group A1 (HMGA1) Proteins

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.

The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development

“…Both Gata-4 and Gata-6 were also reported as genes repressed by Hmga1 in a similar microarray study comparing genes expressed in wildtype mouse embryonic stem cells (mESCs) to mESCs deficient in Hmga1 [198]. The differential regulation of Gata-4 was confirmed by RT-PCR in mESCs and mouse embryo fibroblasts (MEFs), respectively.…”

“…Moreover, Syk is constitutively active in hematologic malignancies and efforts are underway to target its activity in lymphoid malignancies [197]. Syk was reported as a gene induced by Hmga1 in mouse embryo stem cells (mESCs), both in gene expression profile analysis and quantitative RT-PCR studies [198]. …”

“…A comparison of mouse embryonic stem cells (mESCs) deficient in Hmga1 to wildtype mESCs led to the identification of target genes involved in endoderm and mesoderm-drived tissues, including blood cell commitment and [144, 198]. When mESC-derived embryoid bodies (EBs) were cultured in methylcellulose under conditions that enable hematopoietic differentiation, the Hmga1 deficient mESCs were reported to form fewer “hematopoietic EB bodies”, defined as EBs that differentiate into colonies with macrophages, granulocytes, and hemoglobin-producing erythroid precursors.…”

“…Although some studies suggest that it has tumor suppressor function, recent work in prostate cancer indicates that ZIF268 promotes proliferation [203]. A report of gene expression profile analyses and quantitative, RT-PCR in mESCs, MEFs, and liver tissue deficient in Hmga1 compared to wildtype fibroblasts showed that Zif268 is induced by Hmga1 [198]. …”

Ménage à Trois in stress: DAMPs, redox and autophagy

“…The best-studied enhanceosome is located on the interferon β (IFN- β) promoter [37]. Furthermore, several genes are regulated by HMGA1, validated by microarray analysis in embryonic stem (ES) cells bearing one or two disrupted hmga1 alleles [38]. This was further studied in other cell types, including those encoding the interferon γ, interleukin-2 receptor α, E-selectin and insulin receptor [39–42].…”