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    • Available data thus indicate that

    2024-03-21

    Available data thus indicate that there are at least two ways that HMGA proteins can induce localized changes in the chromatin structure of inducible gene promoters, both of which involve positioned nucleosomes that must be “remodeled” before gene transcription can occur. The first mechanism is exemplified by the way in which transcription of the IFN-β gene is activated in virus infected cells. In this case HMGA1 binds to, and coordinates the formation of, an enhanceosome on “naked” promoter DNA that is flanked on either side by two strongly positioned nucleosomes. In uninfected cells, one of these nucleosomes is positioned over the TATA box region, thus inhibiting transcription. Once formed, the IFN-β enhanceosome recruits chromatin modifying and remodeling complexes, the later of which induces sliding of the inhibitory nucleosome and exposure of the TATA box so that TBP/TFIID can bind and PolII transcription can be initiated. The second mechanism is epitomized by the way in which the promoters of the IL-2, IL-Rα, CRYAB and the 5′ LTR of the HIV-1 virus, are activated. In each of these cases, prior to transcriptional activation, a nucleosome is stably positioned on a regulatory DNA element that contains TCEP for transcription factors (e.g., HMGA1, Elf-1, AP-1, etc.) that are required for enhanceosome formation. Hall marks of these positioned nucleosomes include (i) the binding site for a sequence-recognizing transcription factor involved is occluded, thereby preventing its binding; (ii) there are one or more stretches of A/T-rich DNA position either on the surface of the nucleosome and/or adjacent to one of its edges; and (iii) the binding sites for HMGA1 and the transcription factor involved frequently overlap and often extending into the adjacent linker region. The roles played by HMGA1 in the disruption of such inhibitory nucleosomes appear to include binding to the A/T-rich regions, recruitment of chromatin remodeling complexes and enhancement of their activity plus participation in enhanceosome formation on, or overlapping, the original site of the positioned core particle.
    HMGA proteins and global chromatin structure In addition to affects on localized nucleosome structure, it has long been appreciated that HMGA proteins also significantly influence larger scale chromatin domains and even the structure of whole chromosomes. For example, soon after their discovery in HeLa cell extracts [95], HMGA1 proteins were demonstrated to specifically bind to the highly repetitive A/T-rich alpha-satellite DNA found in monkey cells [153], suggesting that they might be integral components of chromatin structure. That this is indeed the case was subsequently confirmed by immunofluorescence staining studies demonstrating that HMGA proteins are localized to the A/T-rich G/Q- and C-bands of human and mouse metaphase chromosomes [43]. Their localization to specific regions of metaphase chromosomes led to the prediction that HMGA1 proteins are actively involved in the dynamic changes in chromatin structure that accompany the chromosome condensation and cell division cycles [43], a suggestion that is supported by a substantial body of evidence (reviewed in [140]). For example , it has been demonstrated that treatment of cells with either distamycin A or Hoechst 33258, minor groove binding chemicals that directly compete with the HMGA proteins for binding to AT-DNA in vitro[164], prevents complete condensation of metaphase chromosomes in vivo[129]. Likewise, HMGA1 proteins have been demonstrated to be in vivo substrates for cdc2 kinase which phosphorylates specific threonine residues located adjacent to two of the three AT-hooks of the protein during the G2/M phase of the cell cycle. These phosphorylations reduce the binding affinity of the modified HMGA1 proteins for A/T-rich DNA by more that 20-fold [109,136] and are likely to be associated with the marked changes in chromosome structure and dynamic protein interactions that are occurring during the G2/M phase of the cell cycle. Additionally, these modifications may also be associated with the reversible shuttling of a subpopulation of HMGA1 proteins between the nucleus and mitochondria that occurs around this stage of the cell cycle in normal cells [40,98].