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Genome-wide CIITA-binding profile identifies sequence preferences that dictate function versus recruitment.

Scharer CD, Choi NM, Barwick BG, Majumder P, Lohsen S, Boss JM - Nucleic Acids Res. (2015)

Bottom Line: Nearly all CIITA-bound sites were within regions containing accessible chromatin, and CIITA's presence at these sites was associated with increased histone H3K27 acetylation, suggesting that CIITA's role at these non-regulated loci may be to poise the region for subsequent regulation.Computational genome-wide modeling of the CIITA bound XY box motifs provided constraints for sequences associated with CIITA-mediated gene regulation versus binding.These data therefore define the CIITA regulome in B cells and establish sequence specificities that predict activity for an essential regulator of the adaptive immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.

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XY box sequence length and motif score distinguish binding from regulatory function. (A) The relationship between the XY box motif score and motif length was plotted for 479 sequences in CIITA-binding sites that matched the XY box PWM model generated in Figure 6A. Gene expression data was integrated and color-coded according to the grouping in Table 1. The size of each circle is proportional to the fold change in RJ2.2.5 from Raji. Ten base pair phasing of XY box lengths that correlate with MHC-II promoters are shaded in green. (B) Scatter plots of XY box motif score and change in ATAC-seq and H3K27ac reads at 479 CIITA-binding sites. Read differences were determined by subtracting the average rpm in 1 kb windows surrounding each CIITA peak in Raji from RJ2.2.5 cells. The color density of each point corresponds to motif score. The linear regression of the correlation of rpm differences with XY box score is plotted in green with the P-value denoting the significance of the correlation. (C) Venn diagram representing the number of RFX5, CREB1, and NF-YB bound sites identified by ChIP-seq from GM12878 cells from the ENCODE Consortium (42) that co-occurred in a 100 bp window. (D) Density scatter plot of XY box motif score versus motif length for sites identified in (B) that matched the XY box model generated in Figure 6A. Sites that mapped to an MHC-II gene are indicated by green open circles.
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Figure 7: XY box sequence length and motif score distinguish binding from regulatory function. (A) The relationship between the XY box motif score and motif length was plotted for 479 sequences in CIITA-binding sites that matched the XY box PWM model generated in Figure 6A. Gene expression data was integrated and color-coded according to the grouping in Table 1. The size of each circle is proportional to the fold change in RJ2.2.5 from Raji. Ten base pair phasing of XY box lengths that correlate with MHC-II promoters are shaded in green. (B) Scatter plots of XY box motif score and change in ATAC-seq and H3K27ac reads at 479 CIITA-binding sites. Read differences were determined by subtracting the average rpm in 1 kb windows surrounding each CIITA peak in Raji from RJ2.2.5 cells. The color density of each point corresponds to motif score. The linear regression of the correlation of rpm differences with XY box score is plotted in green with the P-value denoting the significance of the correlation. (C) Venn diagram representing the number of RFX5, CREB1, and NF-YB bound sites identified by ChIP-seq from GM12878 cells from the ENCODE Consortium (42) that co-occurred in a 100 bp window. (D) Density scatter plot of XY box motif score versus motif length for sites identified in (B) that matched the XY box model generated in Figure 6A. Sites that mapped to an MHC-II gene are indicated by green open circles.

Mentions: To examine how motif score and XY box length correlate, all 479 PWM CIITA-binding sites were analyzed (Figure 7A). Human MHC-II genes contained the highest scoring motifs with a total length ranging from 47 to 49 bp. CIITA sites outside of the MHC-II locus identified previously by ChIP-chip (26) also fell within a narrow window consistent with a defined spatial requirement of XY boxes (18). With the exception of MKNK2, all of Group I genes had spacing that matched the MHC-II phasing/periodicity previously described for the HLA-DRA XY box (18). Thus, the CIITA regulated genes display distinct spacing/phasing that separates this group of genes from those that recruit CIITA.


Genome-wide CIITA-binding profile identifies sequence preferences that dictate function versus recruitment.

Scharer CD, Choi NM, Barwick BG, Majumder P, Lohsen S, Boss JM - Nucleic Acids Res. (2015)

XY box sequence length and motif score distinguish binding from regulatory function. (A) The relationship between the XY box motif score and motif length was plotted for 479 sequences in CIITA-binding sites that matched the XY box PWM model generated in Figure 6A. Gene expression data was integrated and color-coded according to the grouping in Table 1. The size of each circle is proportional to the fold change in RJ2.2.5 from Raji. Ten base pair phasing of XY box lengths that correlate with MHC-II promoters are shaded in green. (B) Scatter plots of XY box motif score and change in ATAC-seq and H3K27ac reads at 479 CIITA-binding sites. Read differences were determined by subtracting the average rpm in 1 kb windows surrounding each CIITA peak in Raji from RJ2.2.5 cells. The color density of each point corresponds to motif score. The linear regression of the correlation of rpm differences with XY box score is plotted in green with the P-value denoting the significance of the correlation. (C) Venn diagram representing the number of RFX5, CREB1, and NF-YB bound sites identified by ChIP-seq from GM12878 cells from the ENCODE Consortium (42) that co-occurred in a 100 bp window. (D) Density scatter plot of XY box motif score versus motif length for sites identified in (B) that matched the XY box model generated in Figure 6A. Sites that mapped to an MHC-II gene are indicated by green open circles.
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Figure 7: XY box sequence length and motif score distinguish binding from regulatory function. (A) The relationship between the XY box motif score and motif length was plotted for 479 sequences in CIITA-binding sites that matched the XY box PWM model generated in Figure 6A. Gene expression data was integrated and color-coded according to the grouping in Table 1. The size of each circle is proportional to the fold change in RJ2.2.5 from Raji. Ten base pair phasing of XY box lengths that correlate with MHC-II promoters are shaded in green. (B) Scatter plots of XY box motif score and change in ATAC-seq and H3K27ac reads at 479 CIITA-binding sites. Read differences were determined by subtracting the average rpm in 1 kb windows surrounding each CIITA peak in Raji from RJ2.2.5 cells. The color density of each point corresponds to motif score. The linear regression of the correlation of rpm differences with XY box score is plotted in green with the P-value denoting the significance of the correlation. (C) Venn diagram representing the number of RFX5, CREB1, and NF-YB bound sites identified by ChIP-seq from GM12878 cells from the ENCODE Consortium (42) that co-occurred in a 100 bp window. (D) Density scatter plot of XY box motif score versus motif length for sites identified in (B) that matched the XY box model generated in Figure 6A. Sites that mapped to an MHC-II gene are indicated by green open circles.
Mentions: To examine how motif score and XY box length correlate, all 479 PWM CIITA-binding sites were analyzed (Figure 7A). Human MHC-II genes contained the highest scoring motifs with a total length ranging from 47 to 49 bp. CIITA sites outside of the MHC-II locus identified previously by ChIP-chip (26) also fell within a narrow window consistent with a defined spatial requirement of XY boxes (18). With the exception of MKNK2, all of Group I genes had spacing that matched the MHC-II phasing/periodicity previously described for the HLA-DRA XY box (18). Thus, the CIITA regulated genes display distinct spacing/phasing that separates this group of genes from those that recruit CIITA.

Bottom Line: Nearly all CIITA-bound sites were within regions containing accessible chromatin, and CIITA's presence at these sites was associated with increased histone H3K27 acetylation, suggesting that CIITA's role at these non-regulated loci may be to poise the region for subsequent regulation.Computational genome-wide modeling of the CIITA bound XY box motifs provided constraints for sequences associated with CIITA-mediated gene regulation versus binding.These data therefore define the CIITA regulome in B cells and establish sequence specificities that predict activity for an essential regulator of the adaptive immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.

Show MeSH
Related in: MedlinePlus