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  • Consistent with the above prediction

    2024-02-10

    Consistent with the above prediction, there are additional reports in which HMGA proteins have been demonstrated to facilitate recruitment of chromatin remodeling complexes to gene regulatory regions containing positioned nucleosomes during the transcriptional activation process. One particularly illuminating example involves the transcriptional activation of the latent immunodeficiency virus type 1 (HIV-1) provirus in human cells, a process that involves HMGA1 [64]. Following HIV-1 integration into the genome, the 5′ long terminal repeat (LTR) is packaged into an array of nucleosomes specifically positioned with respect to DNA sequence elements that regulate the transcriptional activity of the provirus. One of these nucleosomes, nuc-1, is positioned immediately 3′-downstream of the transcription start site and inhibits proviral expression. Interestingly, the DNA encompassed by nuc-1 contains two A/T-rich stretches that are strong HMGA1 binding sites, one located on the surface of the nucleosome and the other that is situated at the 3′ exit of DNA from the core particle and which overlaps an AP1-3/ATF-3 transcription factor binding site that extends into the linker region [64]. Agents, such as phorbol esters, that stimulate T cell activation not only rapidly induce HMGA1 expression [34,55,111] but also lead to rapid disruption of nuc-1 and stimulation of HIV-1 proviral transcription [64]. Experiments have demonstrated that following treatment of Jurkat T A-54556A with phorbol myristate acetate, the transcription factors ATF-3 and JunB as well as BRG-1 (the ATPase subunit of the human SWI/SNF chromatin remodeling complex) are recruited to the 3′ boundary of nuc-1 whereupon the nucleosome is disrupted. Analysis of this recruitment process revealed that ATF-3 and BRG-1 exist together as a complex and that it is ATF-3 that is responsible for targeting the human SWI/SNF (hSWI/SNF) to the overlapping HMGA1/ATF-3 site at the edge of the core particle. Importantly, though, it was also demonstrated that HMGA1 proteins are required for recruitment of hSWI/SNF to the nuc-1 nucleosome [65]. Activation of the human alpha-B-crystallin (CRYAB) gene is another well-documented example in which HMGA1 has been demonstrated to play a crucial role in recruiting both BRG-1 and AP-1 to a positioned nucleosome on the gene's promoter that is remodeled during transcriptional initiation. CRYAB is a small heat-shock protein that is expressed at high levels in vertebrate eyes and which has been implicated in many cellular processes including the phenotypic changes associated with lens cell differentiation. Transcriptional activation of CRYAB has been demonstrated to depend on either BRG-1 containing, or hBRM-associated factor (BAF) containing, SWI/SNF chromatin remodeling complexes [90]. Recently, Duncan and Zhao [44] identified a 30-bp DNA element in the gene's promoter situated between −90 to −60 bp immediately upstream from the start site that is responsible for BRG-1-mediated activation of CRYAB transcription and whose action is chromatin dependent. Point mutagenesis studies demonstrated that this BRG-1 response element contains an A/T-rich site for HMGA binding and a consensus recognition site for the AP-1 transcription factor. Ligation-mediated PCR (LM-PCR) analyses demonstrated that this response element was located at the edge of a positioned nucleosome in non-BRG-1-expressing cells in vivo. Electrophoretic mobility “supershift” analyses of extracts from BRG-1-expressing cells and chromatin immunoprecipitation (ChIP) analyses of CRYAB-expressing cells demonstrated that HMGA1 binds to the response element both in vitro and in vivo. And finally, cell transfection experiments employing small hairpin RNAs demonstrated that HMGA1 proteins are critically required for the maximal activation of the CRYAB promoter by BRG-1. Based on these data, the authors concluded that HMGA1, a BRG-1 containing SWI/SNF chromatin remodeling complex, and the sequence-specific transcription factors AP-1 act together to regulate maximal expression of the CRYAB gene in vivo. They further suggest that the most likely function of the HMGA1 protein is to facilitate and assist remodeling of the inhibitory nucleosome by the BRG-1/SWI/SNF complex [44].