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Mol Cell Biol, April 1998, p. 2173-2183, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Sequence Divergence in the 3' Untranslated Regions of Human zeta - and alpha -Globin mRNAs Mediates a Difference in Their Stabilities and Contributes to Efficient alpha -to-zeta Gene Developmental Switching

J. Eric Russell,1,2,* Julia Morales,1,3 Aleksandr V. Makeyev,1,3 and Stephen A. Liebhaber1,2,3

Howard Hughes Medical Institute3 and Departments of Genetics1 and Medicine (Hematology/Oncology),2 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Received 27 October 1997/Returned for modification 18 December 1997/Accepted 20 January 1998

The developmental stage-specific expression of human globin proteins is characterized by a switch from the coexpression of zeta - and alpha -globin in the embryonic yolk sac to exclusive expression of alpha -globin during fetal and adult life. Recent studies with transgenic mice demonstrate that in addition to transcriptional control elements, full developmental silencing of the human zeta -globin gene requires elements encoded within the transcribed region. In the current work, we establish that these latter elements operate posttranscriptionally by reducing the relative stability of zeta -globin mRNA. Using a transgenic mouse model system, we demonstrate that human zeta -globin mRNA is unstable in adult erythroid cells relative to the highly stable human alpha -globin mRNA. A critical determinant of the difference between alpha - and zeta -globin mRNA stability is mapped by in vivo expression studies to their respective 3' untranslated regions (3'UTRs). In vitro messenger ribonucleoprotein (mRNP) assembly assays demonstrate that the alpha - and zeta -globin 3'UTRs assemble a previously described mRNP stability-determining complex, the alpha -complex, with distinctly different affinities. The diminished efficiency of alpha -complex assembly on the zeta  3'UTR results from a single Cright-arrowG nucleotide substitution in a crucial polypyrimidine tract contained by both the human alpha - and zeta -globin mRNA 3'UTRs. A potential pathway for accelerated zeta -globin mRNA decay is suggested by the observation that its 3'UTR encodes a shortened poly(A) tail. Based upon these data, we propose a model for zeta -globin gene silencing in fetal and adult erythroid cells in which posttranscriptional controls play a central role by providing for accelerated clearance of zeta -globin transcripts.

* Corresponding author. Mailing address: Abramson Research Building, Room 316F, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Phone: (215) 590-3880. Fax: (215) 590-4834. E-mail: jeruss{at}mail.med.upenn.edu.




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