Polycomb recruitment at the Class II transactivator gene.
The Class II Transactivator (CIITA) is the master regulator of Major Histocompatibility Class II (MHC II) genes. Transcription of CIITA through the IFN-γ inducible CIITA promoter IV (CIITA pIV) during activation is characterized by a decrease in trimethylation of histone H3 lysine 27 (H3K27me3), catalyzed by the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2). While EZH2 is the known catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is present at the inactive CIITA pIV, the mechanism of PRC2 recruitment to mammalian promoters remains unknown. Here we identify two DNA-binding proteins, which interact with and regulate PRC2 recruitment to CIITA pIV. We demonstrate Yin Yang 1 (YY1) and Jumonji domain containing protein 2 (JARID2) are binding partners along with EZH2 in mammalian cells. Upon IFN-γ stimulation, YY1 dissociates from CIITA pIV while JARID2 binding to CIITA pIV increases, suggesting novel roles for these proteins in regulating expression of CIITA pIV. Knockdown of YY1 and JARID2 yields decreased binding of EZH2 and H3K27me3 at CIITA pIV, suggesting important roles for YY1 and JARID2 at CIITA pIV. JARID2 knockdown also results in significantly elevated levels of CIITA mRNA upon IFN-γ stimulation. This study is the first to identify novel roles of YY1 and JARID2 in the epigenetic regulation of the CIITA pIV by recruitment of PRC2. Our observations indicate the importance of JARID2 in CIITA pIV silencing, and also provide a novel YY1-JARID2-PRC2 regulatory complex as a possible explanation of differential PRC2 recruitment at inducible versus permanently silenced genes.
Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, GA 30302, United States. Electronic address: nboyd3@gsu.edu.
Nathaniel H
NH
Boyd
Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, GA 30302, United States. Electronic address: jmorgan30@gsu.edu.
Julie E
JE
Morgan
Department of Biology, Georgia State University, Petit Science Center, 100 Piedmont Avenue, Suite 632, Atlanta, GA 30302-4010, United States. Electronic address: sgreer@gsu.edu.
Susanna F
SF
Greer
D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism
D006657:Histones; C093650:Jarid2 protein, mouse; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D050986:YY1 Transcription Factor; D007371:Interferon-gamma; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine
CIITA; EZH2; JARID2; Polycomb recruitment; YY1