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RNA-Mediated Regulation of HMGA1 Function.

Benecke AG, Eilebrecht S - Biomolecules (2015)

Bottom Line: HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression.Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression.In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases.

View Article: PubMed Central - PubMed

ABSTRACT
The high mobility group protein A1 (HMGA1) is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression. Apart from its significant expression during development, HMGA1 is over-expressed in virtually every cancer, where HMGA1 expression levels correlate with tumor malignancy. The exogenous overexpression of HMGA1 can lead to malignant cell transformation, assigning the protein a key role during cancerogenesis. Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression. In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases.

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Related in: MedlinePlus

Schematic view of HMGA1 functional domains and RNA interfaces. (A) Schematic view of the HMGA1a/b functional domains. Interaction sites with transcription factors are labeled in black, the interface with 7SK and TAR RNA is depicted in blue/green; (B) Secondary structures of 7SK Loop2 (green) and HIV-1 TAR RNA (blue). The specific HMGA1-binding structures are highlighted in red.
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biomolecules-05-00943-f002: Schematic view of HMGA1 functional domains and RNA interfaces. (A) Schematic view of the HMGA1a/b functional domains. Interaction sites with transcription factors are labeled in black, the interface with 7SK and TAR RNA is depicted in blue/green; (B) Secondary structures of 7SK Loop2 (green) and HIV-1 TAR RNA (blue). The specific HMGA1-binding structures are highlighted in red.

Mentions: HMGA1 belongs to the high mobility group (HMG) protein family, comprising a variety of non-histone proteins involved in global chromatin remodeling [1]. Within this family, the HMGA proteins are characterized by the presence of three AT-hook DNA binding motifs containing the core peptide Pro-Arg-Gly-Arg-Pro (P-R-G-R-P), allowing them to preferentially bind to the minor groove of A/T-rich B-form DNA sequences [2]. Though all three motifs synergize during target recognition, the first two AT-hooks contribute the majority of HMGA1’s DNA affinity [3]. HMGA1 proteins act as antagonists of the linker histone H1, which binds to the same DNA sequences and maintains chromatin in a tightly packed, transcription-inactive state [4]. Thus, HMGA1 proteins introduce major changes in DNA structure, resulting in a more open chromatin state, which facilitates gene transcription (Figure 1). Apart from this global role as master regulators of chromatin structure, HMGA1 proteins physically interact with a large variety of different transcription factors, such as Sp1, NF-κB, NF-Y, ATF-2, c-Jun, TAF3, p150 and others [5,6,7,8], orchestrating their assembly at gene promoter and enhancer regions, also assigning them important functions during gene-specific transcription regulation (Figure 1). The HMGA1 gene encodes for two alternatively spliced isoforms HMGA1a and HMGA1b, the latter one lacking 11 amino acids between the first and the second AT-hook motif [9,10] (Figure 2A).


RNA-Mediated Regulation of HMGA1 Function.

Benecke AG, Eilebrecht S - Biomolecules (2015)

Schematic view of HMGA1 functional domains and RNA interfaces. (A) Schematic view of the HMGA1a/b functional domains. Interaction sites with transcription factors are labeled in black, the interface with 7SK and TAR RNA is depicted in blue/green; (B) Secondary structures of 7SK Loop2 (green) and HIV-1 TAR RNA (blue). The specific HMGA1-binding structures are highlighted in red.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496703&req=5

biomolecules-05-00943-f002: Schematic view of HMGA1 functional domains and RNA interfaces. (A) Schematic view of the HMGA1a/b functional domains. Interaction sites with transcription factors are labeled in black, the interface with 7SK and TAR RNA is depicted in blue/green; (B) Secondary structures of 7SK Loop2 (green) and HIV-1 TAR RNA (blue). The specific HMGA1-binding structures are highlighted in red.
Mentions: HMGA1 belongs to the high mobility group (HMG) protein family, comprising a variety of non-histone proteins involved in global chromatin remodeling [1]. Within this family, the HMGA proteins are characterized by the presence of three AT-hook DNA binding motifs containing the core peptide Pro-Arg-Gly-Arg-Pro (P-R-G-R-P), allowing them to preferentially bind to the minor groove of A/T-rich B-form DNA sequences [2]. Though all three motifs synergize during target recognition, the first two AT-hooks contribute the majority of HMGA1’s DNA affinity [3]. HMGA1 proteins act as antagonists of the linker histone H1, which binds to the same DNA sequences and maintains chromatin in a tightly packed, transcription-inactive state [4]. Thus, HMGA1 proteins introduce major changes in DNA structure, resulting in a more open chromatin state, which facilitates gene transcription (Figure 1). Apart from this global role as master regulators of chromatin structure, HMGA1 proteins physically interact with a large variety of different transcription factors, such as Sp1, NF-κB, NF-Y, ATF-2, c-Jun, TAF3, p150 and others [5,6,7,8], orchestrating their assembly at gene promoter and enhancer regions, also assigning them important functions during gene-specific transcription regulation (Figure 1). The HMGA1 gene encodes for two alternatively spliced isoforms HMGA1a and HMGA1b, the latter one lacking 11 amino acids between the first and the second AT-hook motif [9,10] (Figure 2A).

Bottom Line: HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression.Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression.In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases.

View Article: PubMed Central - PubMed

ABSTRACT
The high mobility group protein A1 (HMGA1) is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression. Apart from its significant expression during development, HMGA1 is over-expressed in virtually every cancer, where HMGA1 expression levels correlate with tumor malignancy. The exogenous overexpression of HMGA1 can lead to malignant cell transformation, assigning the protein a key role during cancerogenesis. Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression. In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases.

Show MeSH
Related in: MedlinePlus