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Core histones package the genome into nucleosomes and control its accessibility to transcription factors. High mobility group proteins (HMGs) are, after histones, the second most abundant chromatin proteins and exert global genomic functions in establishing active or inactive chromatin domains. It is becoming increasingly clear that they also specifically control the expression of a limited number of genes. Moreover, they contribute to the fine tuning of transcription in response to rapid environmental changes. They do so by interacting with nucleosomes, transcription factors, nucleosome-remodelling machines, and with histone H1. [Copyright &y& Elsevier]

High mobility group (HMG) proteins are chromatin proteins endowed with ‘architectural’ capabilities. HMGA proteins are moderately sequence-specific, and help build enhanceosomes by interacting with partner proteins and binding stably to the minor groove of DNA; their acetylation/deacetylation signal enhanceosome assembly or disassembly. HMGBs are much more dynamic proteins: they have no sequence specificity, and help transcription factors and other nuclear proteins bind to their cognate sites by bending the DNA molecule. However, HMGBs are rarely retained within the complex. Similarly, HMGBs interact with nucleosomes and promote their sliding, but remain bound only for fractions of a second. We argue that HMGBs fluidize chromatin — an action that appears opposite to that of histone H1. [Copyright &y& Elsevier]

Induction of isotype switching to a specific CH gene correlates with the transcriptional activation of the same gene in germline (GL) configuration. Expression of correctly spliced GL transcripts is necessary to target a switch region for recombination. In human B cells, the IgE and IgG4 isotypes are both induced by IL-4 through sequential switching, but are functionally antagonistic because IgG4 appears to have IgE-blocking activity. In order to understand the molecular mechanisms that regulate IgG4 production, we undertook a systematic analysis of the γ4 GL promoter. A HindIII/NaeI region (−421/+474) highly conserved in the human γ locus mediated the synergistic activation of a reporter gene in response to IL-4 and CD40 cross-linking. STAT6 binding to the proximal γ4 GL promoter was essential for both IL-4-induced activation and CD40-dependent enhancement of transcription. Of note, a 45 bp region (−76/−32) centered around the STAT6 binding motif drove robust synergistic activation of a heterologous fos promoter upon stimulation with IL-4 and CD40 cross-linking. This finding suggested that the (−76/−32) region may contain a novel IL-4/CD40 responsive element (RE). Electrophoretic mobility shift assays (EMSA) analysis using BL-2 nuclear extracts and in vitro translated NF-κB/Rel family proteins revealed the presence of a motif that overlaps the 5′ end of the STAT6 element and binds selectively c-Rel. A mutation that abrogated c-Rel, but not STAT6, binding strongly impaired the CD40-induced enhancement of IL-4-dependent γ4 GL transcription in reporter assays. These results indicate that c-Rel is selectively involved in the CD40-dependent activation of the IL-4/CD40 RE in the proximal γ4 GL promoter. [Copyright &y& Elsevier]