Tissue-Specific Chromatin Modifications at a Multigene Locus Generate Asymmetric Transcriptional Interactions

Abstract

Random assortment within mammalian genomes juxtaposes genes with distinct expression profiles. This organization, along with the prevalence of long-range regulatory controls, generates a potential for aberrant transcriptional interactions. The human CD79b/GH locus contains six tightly linked genes with three mutually exclusive tissue specificities and interdigitated control elements. One consequence of this compact organization is that the pituitary cell-specific transcriptional events that activate hGH-N also trigger ectopic activation of CD79b. However, the B-cell-specific events that activate CD79b do not trigger reciprocal activation of hGH-N. Here we utilized DNase I hypersensitive site mapping, chromatin immunoprecipitation, and transgenic models to explore the basis for this asymmetric relationship. The results reveal tissue-specific patterns of chromatin structures and transcriptional controls at the CD79b/GH locus in B cells distinct from those in the pituitary gland and placenta. These three unique transcriptional environments suggest a set of corresponding gene expression pathways and transcriptional interactions that are likely to be found juxtaposed at multiple sites within the eukaryotic genome.

Epigenetic Activation of the Human Growth Hormone Gene Cluster during Placental Cytotrophoblast Differentiation

“…A human bacterial artificial chromosome (BAC) genomic clone encompassing the hGH LCR and the entire hGH cluster was identified by a screen of a total genomic library (CITB Human B&C Library; Invitrogen Life Technologies) with probes corresponding to the TCAM1 and SCN4A genes (69). A 148.3-kb clone (clone 535D15) was identified, and a 123-kb insert was released by NotI digestion.…”

A 914-bp promoter is sufficient to reproduce the endogenous prolyl oligopeptidase gene localization in the mouse placenta if not subject to position effect

“…Some promoters have an almost complete set of elements to fully activate the gene (Kamat et al, 1999;Klüppel et al, 1991;Rao et al, 2003;Reddi et al, 2007;Yoo et al, 2006), but others have little activity (Grosveld et al, 1987;Heckert et al, 2000;Jones et al, 1995). Therefore, it is very important to evaluate the promoter activity of each gene, and we analyzed the in vivo activity of the POP promoter for the first time by using transgenic mice.…”

“…Previous reports have shown that some promoters had sufficient activity to drive the appropriate gene expression in transgenic mice. For example, promoters of the Pem/Rhox5 gene (Rao et al, 2003), the CYP19 aromatase gene (Kamat et al, 1999), the tyrosinase gene (Klüppel et al, 1991), and the human Ig gene (Yoo et al, 2006) reproduced the tissue-specific expression patterns of the corresponding genes in transgenic mice. Several testis-specific promoters have also been reported to be sufficient for the appropriate gene activation in transgenic mice (Reddi et al, 2007).…”

Identification of a Secondary Promoter within the Human B Cell Receptor Component Gene hCD79b

“…On the basis of these early studies, it was concluded that this promoter region, along with its linked enhancer/repressor elements, constituted the core determinants of hCD79b transcriptional control (12). However, subsequent in vivo analyses of hCD79b gene expression using transgenic mouse models have brought into question whether these elements have essential roles in the expression of the hCD79b locus in its native genome environment (13).…”

“…This complex locus contains multiple DNase I HSs with distinct tissue and developmental specificities (13,(27)(28)(29). The HSs in this region that form in pituitary somatotropes, placental syncytiotrophoblasts, skin fibroblasts, and B lymphocytes have been extensively explored and identified by the combined analyses of chromatin from corresponding cell lines, primary human tissues, and human loci carried in defined transgenic mouse lines (13). These patterns of HSs point to a complex, tissue-specific set of cis-acting elements that are alternatively used to drive mutually exclusive patterns of gene expression in these distinct tissues.…”