Adult Stage Gamma-globin Silencing is Mediated by a Promoter Direct Repeat Element

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2005 Apr 16

PMID 15831451

Citations 24

Authors

Akane Omori

Osamu Tanabe

James Douglas Engel

Akiyoshi Fukamizu

Keiji Tanimoto

Affiliations

Soon will be listed here.

Abstract

The human beta-like globin genes (5'-epsilon-Ggamma-Agamma-delta-beta-3') are temporally expressed in sequential order from the 5' to 3' end of the locus, but the nonadult epsilon- and gamma-globin genes are autonomously silenced in adult erythroid cells. Two cis elements have been proposed to regulate definitive erythroid gamma-globin repression: the DR (direct repeat) and CCTTG elements. Since these two elements partially overlap, and since a well-characterized HPFH point mutation maps to an overlapping nucleotide, it is not clear if both or only one of the two participate in gamma-globin silencing. To evaluate the contribution of these hypothetical silencers to gamma-globin regulation, we generated point mutations that individually disrupted either the single DR or all four CCTTG elements. These two were separately incorporated into human beta-globin yeast artificial chromosomes, which were then used to generate gamma-globin mutant transgenic mice. While DR element mutation led to a dramatic increase in Agamma-globin expression only during definitive erythropoiesis, the CCTTG mutation did not affect adult stage transcription. These results demonstrate that the DR sequence element autonomously mediates definitive stage-specific gamma-globin gene silencing.

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