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Global Regulation by the Yeast Spt10 Protein Is Mediated through Chromatin Structure and the Histone Upstream Activating Sequence Elements

Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Building 6A, Room 2A14, 6 Center Drive, Bethesda, Maryland 20892,¹ National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894,² Department of Biology, College of Staten Island, CUNY Staten Island, Staten Island, New York 10314,³ National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892⁴

Received 24 May 2005/ Returned for modification 20 June 2005/ Accepted 20 July 2005

The yeast SPT10 gene encodes a putative histone acetyltransferase (HAT) implicated as a global transcription regulator acting through basal promoters. Here we address the mechanism of this global regulation. Although microarray analysis confirmed that Spt10p is a global regulator, Spt10p was not detected at any of the most strongly affected genes in vivo. In contrast, the presence of Spt10p at the core histone gene promoters in vivo was confirmed. Since Spt10p activates the core histone genes, a shortage of histones could occur in spt10 cells, resulting in defective chromatin structure and a consequent activation of basal promoters. Consistent with this hypothesis, the spt10 phenotype can be rescued by extra copies of the histone genes and chromatin is poorly assembled in spt10 cells, as shown by irregular nucleosome spacing and reduced negative supercoiling of the endogenous 2µm plasmid. Furthermore, Spt10p binds specifically and highly cooperatively to pairs of upstream activating sequence elements in the core histone promoters [consensus sequence, (G/A)TTCCN₆TTCNC], consistent with a direct role in histone gene regulation. No other high-affinity sites are predicted in the yeast genome. Thus, Spt10p is a sequence-specific activator of the histone genes, possessing a DNA-binding domain fused to a likely HAT domain.

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