p21(WAF1) gene promoter is epigenetically silenced by CTIP2 and SUV39H1.
Mainly regulated at the transcriptional level, the cellular cyclin-dependent kinase inhibitor, CDKN1A/p21(WAF1) (p21), is a major cell cycle regulator of the response to DNA damage, senescence and tumor suppression. Here, we report that COUP-TF-interacting protein 2 (CTIP2), recruited to the p21 gene promoter, silenced p21 gene transcription through interactions with histone deacetylases and methyltransferases. Importantly, treatment with the specific SUV39H1 inhibitor, chaetocin, repressed histone H3 lysine 9 trimethylation at the p21 gene promoter, stimulated p21 gene expression and induced cell cycle arrest. In addition, CTIP2 and SUV39H1 were recruited to the silenced p21 gene promoter to cooperatively inhibit p21 gene transcription. Induction of p21(WAF1) gene upon human immunodeficiency virus 1 (HIV-1) infection benefits viral expression in macrophages. Here, we report that CTIP2 further abolishes Vpr-mediated stimulation of p21, thereby indirectly contributing to HIV-1 latency. Altogether, our results suggest that CTIP2 is a constitutive p21 gene suppressor that cooperates with SUV39H1 and histone methylation to silence the p21 gene transcription.
Cherrier
T
T
Université de Strasbourg, Institut de Virologie, France.
Suzanne
S
S
Redel
L
L
Calao
M
M
Marban
C
C
Samah
B
B
Mukerjee
R
R
Schwartz
C
C
Gras
G
G
Sawaya
B E
BE
Zeichner
S L
SL
Aunis
D
D
Van Lint
C
C
Rohr
O
O
D002453:Cell Cycle; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000821:virology; D008780:Methyltransferases / Q000502:physiology*; D017628:Microglia / Q000821:virology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D014779:Virus Replication; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000502:physiology
C479740:BCL11B protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; C407843:SUV39H1 protein, human; D008780:Methyltransferases