X box-like sequences in the MHC class II region maintain regulatory function.
Sequences homologous to the canonical MHC class II (MHC-II) gene X box regulatory elements were identified within the HLA-DR subregion of the human MHC and termed X box-like (XL) sequences. Several XL box sequences were found to bind the MHC class II-specific transcription factors regulatory factor X and CIITA and were transcriptionally active. The histone code associated with the XL boxes and that of the HLA-DRA X box was determined. Using CIITA-positive and -negative B cell lines, CIITA-specific histone modifications were identified and found to be consistent among the active XL boxes. Although a remarkable similarity was observed for most modifications, differences in magnitude between the HLA-DRA promoter for modifications associated with the assembly of the general transcription factors, such as histone H3 lysine 9 acetylation and H3 lysine 4 trimethylation, distinguished the very active HLA-DRA promoter from the XL box regions. In response to IFN-gamma, XL box-containing histones displayed increased acetylation, coincident with CIITA expression and that observed in B cells, suggesting that the end point mechanisms of chromatin remodeling for cell type-specific MHC-II expression were similar. Lastly, an interaction between one XL box and the HLA-DRA promoter was observed in a chromatin-looping assay. Therefore, these data provide evidence that certain XL box sequences contribute to a global increase in chromatin accessibility of the HLA-DR region in B lymphocytes and in response to IFN-gamma and supports the involvement of these XL sequences in the regulation of MHC-II genes.
Department of Microbiology and Immunology, Emory University School of Medicine, 1600 Clifton Road, Atlanta, GA 30322, USA.
Jorge A
JA
Gomez
Parimal
P
Majumder
Uma M
UM
Nagarajan
Jeremy M
JM
Boss
D000107:Acetylation; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D005802:Genes, MHC Class II; D006681:HLA-D Antigens / Q000235:genetics* / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D059805:HLA-DR alpha-Chains; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009687:Nuclear Proteins / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D000071701:Regulatory Factor X Transcription Factors; D015534:Trans-Activators / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*
D002843:Chromatin; D004268:DNA-Binding Proteins; D006681:HLA-D Antigens; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D006657:Histones; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma