Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein

Abstract

Histone acetyltransferase (HAT) activities of proteins such as p300, CBP, and P/CAF play important roles in activation of gene expression. We now show that the HAT activity of p300 can also be required for down-regulation of transcription by a DNA binding repressor protein. Promyelocytic leukemia zinc finger (PLZF), originally identified as a fusion with retinoic acid receptor alpha in rare cases of all-trans-retinoic acid-resistant acute promyelocytic leukemia, is a transcriptional repressor that recruits histone deacetylasecontaining corepressor complexes to specific DNA binding sites. PLZF associates with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C 2 -H 2 zinc finger motif. An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/ histone deacetylase complexes. This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo. Taken together, our results indicate that a histone deacetylase-dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a coactivator protein in transcriptional repression.Alterations of chromatin structure by covalent modification of nucleosomal histones at specific lysine residues in their amino-terminal tails play a major role in regulation of gene expression (26). Over the past few years, a large number of chromatin-modifying factors and complexes have been identified and characterized (see references 1, 15, and 27) and references therein for reviews). Intrinsic histone acetyltransferase (HAT) activities have been found to be associated with a number of transcriptional coactivator proteins, such as p300 (62) and P/CAF (79) (see also references 12 and 44 for reviews).The results of these studies have provided an explanation for the direct relationship between histone acetylation and gene transcription. However, in addition to histones, acetylation of gene-specific (see below) and basal transcription factors (36) by specific HATs has also been shown to play a role in regulating gene expression. For example, p53 is acetylated at specific lysine residues by p300 in vitro and in vivo (32). Acetylation of p53 contributes to its activation by facilitating a transition to a conformation with a higher affinity to its target DNA (32). Key hematopoietic transcription factors such as GATA1 (9) and ELKF (83) were also shown to be acetylated in their DNA binding domains leading to enhanced DNA binding and transcriptional activation. Acetylation has also been shown to antagonize the activities of transcriptional repressors by inhibiting their association with corepressor proteins (8,35,82). In the case of hypoxia-inducible factor 1␣ (HIF-1␣), acetylation represented a prerequisite for recruitment of the ubiquitin mediated degradation system ...

Involvement of β-catenin and unusual behavior of CBP and p300 in glucocorticosteroid signaling in Schwann cells

“…Several studies suggest that cooperation between ␤-catenin and CBP͞p300 might depend on the cell and promoter context (10,28). Other substrates could be acetylated by p300 like PLZF (39) We provide data strongly supporting the hypothesis of ␤-catenin acting as a coactivator and p300 as a repressor of GR in glial cells. These effects seem not to be specific for the GR ligand, as they could be observed in the presence of both Dex and the GR pure agonist RU28362 (data not shown).…”

p300 provides a corepressor function by cooperating with YY1 and HDAC3 to repress c-Myc

“…In several other cases the mechanism of repression of gene expression by p300 appears to be indirect (Munshi et al, 1998;Waltzer and Bienz, 1998;Poizat et al, 2000;Hong and Chakravarti, 2003;Guidez et al, 2005). However, our studies show that p300 plays a more direct role at the chromatin level in repressing Myc.…”

Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation

“…Mechanisms by which PLZF activity can be regulated through specific post-translational modifications, for example, by acetylation and conjugation to small ubiquitin-like modifier, have been characterized (Kang et al, 2003;Guidez et al, 2005;Chao et al, 2007). However, PLZF has always been described as a phosphoprotein, and modulation of its function through this dynamic modification has not yet been elucidated.…”