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.
Highlights
high mobility group protein A1 (HMGA1) belongs to the high mobility group (HMG) protein family, comprising a variety of non-histone proteins involved in global chromatin remodeling [1]
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]
We have identified highly specific interactions of HMGA1a protein with the nuclear non-coding 7SK RNA and the transactivating response element (TAR) located in the nascent transcript of HIV-1 [23,24,25]. 7SK RNA is a highly abundant RNA Polymerase III transcript in eukaryotic cells, which is a negative regulator of RNA Polymerase II transcription elongation by inactivating the Positive
Summary
HMGA1 belongs to the high mobility group (HMG) protein family, comprising a variety of non-histone proteins involved in global chromatin remodeling [1]. 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-B, NF-Y, ATF-2, c-Jun, TAF3, p150 and others [5,6,7,8], orchestrating their assembly at gene promoter and enhancer regions, assigning them important functions during gene-specific transcription regulation (Figure 1). DNA sequences in gene promoter and enhancer regions It acts as an antagonist of the linker histone H1, resulting in an open chromatin structure, permissive for gene transcription. This review focusses on the structure and function of these HMGA1-RNA complexes as well as their implications in HMGA1-related diseases
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