Regulation of Transcription Factor YY1 by Acetylation and Deacetylation

Abstract

YY1 is a sequence-specific DNA-binding transcription factor that has many important biological roles. It activates or represses many genes during cell growth and differentiation and is also required for the normal development of mammalian embryos. Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor 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 C-terminal region interacted with HDACs, which resulted in stable HDAC activity associated with the YY1 protein. Finally, acetylation of the C-terminal zinc finger domain decreased the DNA-binding activity of YY1. Our findings suggest that in the natural context, YY1 activity is regulated through intricate mechanisms involving negative feedback loops, histone deacetylation, and recognition of the cognate DNA sequence affected by acetylation and deacetylation of the YY1 protein.YY1, also known as ␦, NF-E1, and UCRBP, is a multifunctional transcription factor. It binds, with its four C 2 H 2 zinc fingers, to a specific DNA sequence (CGCCATNTT) located in many different promoters and either activates or represses transcription (for comprehensive reviews, see references 57 and 65). YY1 regulates the expression of both cellular and viral genes, including those encoding c-Myc, c-Fos, p53, ␣-actin, gamma interferon, P5 of adeno-associated virus, E6 and E7 of human papillomavirus (HPV), and a number of other viral long terminal repeats. Many of these gene products have important consequences for cell growth and differentiation (reviewed in reference 57). YY1 is highly conserved among human, mouse, and Xenopus laevis cells, and a Drosophila melanogaster homologue of YY1 exists (6,14,20,47,49,58). Knockout studies show that deletion of YY1 results in periimplantation lethality in mice (13), further demonstrating the importance of YY1 in fundamental biological processes such as development.Various biochemical methods have been employed to dissect the functional domains of YY1 in order to understand how the activity of YY1 is regulated (1, 7, 8, 38-40, 58, 73). It can be summarized that YY1 contains two repression domains, one embedded within residues 170 to 200 and the other overlapping with the C-terminal zinc finger DNA-binding domain. YY1 might also contain an independent activation domain at the N terminus. This modular nature of YY1 supports the idea that YY1 is bifunctional, capable of both activating and repressing transcriptio...

Action of Transcription Factors in the Control of Transferrin Receptor Expression in Human Brain Endothelium

“…31,37 The data presented here show that the normal form of YY1, is associated with repression of HTR expression in non-brain endothelium, whereas expression of the 45 kDa truncated form in brain endothelium is associated with HTR expression. We propose therefore that HTR expression in endothelium depends on a balance of activating and repressing forms of YY1.…”

“…34 YY1 is subject to complex regulatory mechanisms in different cell types which affect its functional activity. 35 The promoter sequences surrounding YY1 binding sites, 15 its relative concentration, 36 or post translational modifications, 37 can determine whether YY1 acts as a repressor or activator. In addition, since the binding motif of YY1 is present in a large number of genes, the regulation conferred by YY1 is probably modulated by association with other cell-type specific proteins, 31 including various cellular factors and adaptor proteins, 35 which are themselves, coactivators, corepressors or transcription factors.…”

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

“…YY1 (yin yang 1) is a sequence-specific DNA-binding protein which either enhances or represses transcription in a cell type -dependent and promoter-specific manner (36). The functions of YY1 are regulated by acetylation and deacetylation, through physical interaction with p300/CBP and HDAC1, HDAC2, or HDAC3 (37,38). Thus, we postulated that Zac1 might function in a similar fashion to YY1, acting as a docking protein for acetylating and deacetylating enzymes onto its specific mammalian promoters.…”

Loss of p53 induces epidermal growth factor receptor promoter activity in normal human keratinocytes

“…We found synergism of YY1 and Sp1 in the activation of the EGFR promoter. In addition, YY1 interacts with the co-activators p300 and P/CAF, which facilitate YY1 activation of transcription by acetylating YY1 and the core histones (Yao et al, 2001). Accordingly, YY1-mediated induction of the EGFR promoter was increased up to fivefold by p300 and to a lesser extent by P/CAF, strongly indicating that YY1 does not act alone to induce EGFR promoter activity (Bheda et al, unpublished).…”