Graduation Year

2001

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Medical Microbiology and Immunology

Major Professor

Edward Seto, Ph.D.

Keywords

Transcription factor, Yy1, Regulation

Abstract

Yin Yang 1 (YY1) is a sequence-specific DNA binding transcription factor that plays an important role in development and differentiation. It activates or represses many genes during cell growth and differentiation and is also required for the normal development of the mammalian embryo. Moreover, it has been shown that YY1 may function as a transcriptional initiator. In this dissertation, regulation of human YY1 is analyzed systematically at three levels: At the genomic level, one major transcriptional initiation site of the YY1 gene was mapped to 478 bp upstream of the ATG translational start site. The YY1 promoter was localized to within 277 bp upstream of the major transcriptional initiation site and was shown to contain multiple binding sites for transcriptional factor Sp1 but lack a consensus TATA box. Overexpression of the adenovirus E1A protein represses expression of the YY1 promoter. At the polypeptide level, the activity of YY1 is regulated through acetylation by p300 and PCAF and deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine/lysine-rich domain of residues 170- 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding domain. Acetylation of the central region was required for the full transcriptional repression activity of YY1 and targeted YY1 for active deacetylation by HDACs. However, the C-terminal region of YY1 could not be deacetylated. Rather, the acetylated Cterminal region interacted with HDACs, which resulted in stable histone deacetylase activity associated with the YY1 protein. Furthermore, acetylation of the C-terminal domain decreased the DNA binding activity of YY1. At the protein complex level, YY1 was shown to form a complex with up to four different proteins consistently throughout different purification methods. These proteins are likely to have important regulatory roles in the transcriptional activity of YY1. Taken together, these findings will provide valuable information to our understanding of the regulatory mechanisms of transcription in general.

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