Abstract:

Random assortment of genes within mammalian genomes establishes the potential for interference between neighboring genes with distinct transcriptional specificities. Long-range transcriptional controls further increase this potential. Exploring this problem is of fundamental importance to understanding gene regulation. In the human genome, the Igbeta (CD79b) gene is situated between the pituitary-specific human growth hormone (hGH) gene and its locus control region (hGH LCR). Igbeta protein is considered B-cell specific; its only known role is in B-cell receptor signaling. Unexpectedly, we found that hIgbeta is transcribed at high levels in the pituitary. This Igbeta transcription is dependent on pituitary-specific epigenetic modifications generated by the hGH LCR. In contrast, expression of Igbeta at its native site in B cells is independent of hGH LCR activity. These studies demonstrated that a gene with tissue-restricted transcriptional determinants (B cell) can be robustly activated in an unrelated tissue (pituitary) due to fortuitous positioning within an active chromatin domain. This 'bystander' gene activation pathway impacts on current concepts of tissue specificity and models of active chromatin domains.

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Bystander gene activation by a locus control region

^{Departments of Genetics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA}

^{Department of Genetics, 428 Clinical Research Building, University of Pennsylvania, 415 Curie Blvd, Philadelphia, PA 19104, USA. Tel.: +1 215 898 7834; Fax: +1 215 573 5157; E-mail:}ude.nnepu.dem.liam@ebahbeil

^{Present address: Ohio State University, Columbus, OH, USA}

Received 2004 Mar 31; Accepted 2004 Jul 21.

Abstract

Random assortment of genes within mammalian genomes establishes the potential for interference between neighboring genes with distinct transcriptional specificities. Long-range transcriptional controls further increase this potential. Exploring this problem is of fundamental importance to understanding gene regulation. In the human genome, the Igβ (CD79b) gene is situated between the pituitary-specific human growth hormone (hGH) gene and its locus control region (hGH LCR). Igβ protein is considered B-cell specific; its only known role is in B-cell receptor signaling. Unexpectedly, we found that hIgβ is transcribed at high levels in the pituitary. This Igβ transcription is dependent on pituitary-specific epigenetic modifications generated by the hGH LCR. In contrast, expression of Igβ at its native site in B cells is independent of hGH LCR activity. These studies demonstrated that a gene with tissue-restricted transcriptional determinants (B cell) can be robustly activated in an unrelated tissue (pituitary) due to fortuitous positioning within an active chromatin domain. This ‘bystander' gene activation pathway impacts on current concepts of tissue specificity and models of active chromatin domains.

Keywords: CD79b, chromatin, Igβ, locus control region, hGH

Abstract

Acknowledgments

We thank Dr Roman Perez-Fernandez (Compostela University) and Dr Peter J Snyder (University of Pennsylvania) for gifts of human pituitary mRNA and pituitary adenoma tissue samples, respectively, and Dr Yugong Ho for the hGH/P1(ΔHSI) transgenic lines. We acknowledge support from the University of Pennsylvania Transgenic Mouse Core (P30DK50306, P30DK19525, P30CA16520), the Morphology Core (P30DK50306), and the Flow Cytometry and Cell Sorting Cores (P30CA16520). We thank Drs Marisa Bartolomei, Thomas Kadesch, and Gerd Blobel and members of the Liebhaber and Cooke laboratories for critical reading of the manuscript. This work was supported by NIH grant HD25147 (NEC and SAL) and by a Leukemia and Lymphoma Society postdoctoral fellowship 5013-03 (IC).

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