Site-specific acetylation of the fetal globin activator NF-E4 prevents its ubiquitination and regulates its interaction with the histone deacetylase, HDAC1.
Acetylation provides one mechanism by which the functional diversity of individual transcription factors can be expanded. This is valuable in the setting of complex multigene loci that are regulated by a limited number of proteins, such as the human beta-globin locus. We have studied the role of acetylation in the regulation of the transcription factor NF-E4, a component of a protein complex that facilitates the preferential expression of the human gamma-globin genes in fetal erythroid cells. We have shown that NF-E4 interacts directly with, and serves as a substrate for, the acetyltransferase co-activator PCAF. Acetylation of NF-E4 is restricted to a single residue (Lys(43)) in the amino-terminal domain of the protein and results in two important functional consequences. Acetylation of NF-E4 prolongs the protein half-life by preventing ubiquitin-mediated degradation. This stabilization is PCAF-dependent, since enforced expression in fetal/erythroid cells of a mutant form of PCAF lacking the histone acetyltransferase domain (PCAFDeltaHAT) decreases NF-E4 stability. Acetylation of Lys(43) also reduces the interaction between NF-E4 and HDAC1, potentially maximizing the activating ability of the factor at the gamma-promoter. These results provide further demonstration that co-activators, such as PCAF, can influence individual transcription factor properties at multiple levels to alter their effects on gene expression.
Zhao
Quan
Q
Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
Cumming
Helen
H
Cerruti
Loretta
L
Cunningham
John M
JM
Jane
Stephen M
SM
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics; D051548:Histone Acetyltransferases; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D005326:Fetal Proteins; D051548:Histone Acetyltransferases; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D014157:Transcription Factors; D025801:Ubiquitin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C063115:enhancer-binding protein NF-E4; C110550:HDAC1 protein, human