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J. Biol. Chem., Vol. 279, Issue 42, 43815-43820, October 15, 2004

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Unique Residues on the H2A.Z Containing Nucleosome Surface Are Important for Xenopus laevis Development^*

Patricia Ridgway, Karl D. Brown, Danny Rangasamy, Ulrica Svensson, and David J. Tremethick

From the John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia

Critical to vertebrate development is a complex program of events that establishes specialized tissues and organs from a single fertilized cell. Transitions in chromatin architecture, through alterations in its composition and modification markings, characterize early development. A variant of the H2A core histone, H2A.Z, is essential for development of both Drosophila and mice. We recently showed that H2A.Z is required for proper chromosome segregation. Whether H2A.Z has additional specific functions during early development remains unknown. Here we demonstrate that depletion of H2A.Z by RNA interference perturbs Xenopus laevis development at gastrulation leading to embryos with malformed, shortened trunks. Consistent with this result, whole embryo in situ hybridization indicates that endogenous expression of H2A.Z is highly enriched in the notochord. H2A.Z modifies the surface of a canonical nucleosome by creating an extended acidic patch and a metal ion-binding site stabilized by two histidine residues. To examine the significance of these specific surface regions in vivo, we investigated the consequences of overexpressing H2A.Z and mutant proteins during X. laevis development. Overexpression of H2A.Z slowed development following gastrulation. Altering the extended acidic patch of H2A.Z reversed this effect. Remarkably, modification of a single stabilizing histidine residue located on the exposed surface of an H2A.Z containing nucleosome was sufficient to disrupt normal trunk formation mimicking the effect observed by RNA interference. Taken together, these results argue that key determinants located on the surface of an H2A.Z nucleosome play an important specific role during embryonic patterning and provide a link between a chromatin structural modification and normal vertebrate development.

Received for publication, July 26, 2004 , and in revised form, August 6, 2004.

^* This work was supported by Australian National Health and Medical Research Project Grants 179823 (to P. R. and D. J. T.) and 224226 (to D. R. and D. J. T.) and Australian Academy of Science visits to Europe Grant RI 146.1 (to P. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

To whom correspondence may be addressed. Tel.: 61-2-61252326; Fax: 61-2-6125-0415; E-mail: David.Tremethick{at}anu.edu.au or Pat. Ridgway{at}anu.edu.au.

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