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Distinct and predictive histone lysine acetylation patterns at promoters, enhancers, and gene bodies.

Rajagopal N, Ernst J, Ray P, Wu J, Zhang M, Kellis M, Ren B - G3 (Bethesda) (2014)

Bottom Line: Unexpectedly, we found that histone acetylation alone performs well in distinguishing these unique genomic regions.Further, we found the association of characteristic acetylation patterns with genic regions and association of chromatin state with splicing.Taken together, our work underscores the diverse functional roles of histone acetylation in gene regulation and provides several testable hypotheses to dissect these roles.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653 Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, California 92037 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.

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Acetylations within the gene body distal to exon–intron boundaries and DNAse-I hypersensitive sites in IMR90. (A) ROC curves showing classification of distal genic regions using all 24 modifications (blue) or only 15 acetylations (green). (B) Out-of-bag variable importance of acetylations in classification of distal genic regions against intergenic regions. (C) Heatmap showing enrichment of acetylations in genic regions as compared with intergenic ones using a Z-score normalized measure. Only certain acetylations show enrichment in a majority of genic regions as compared with intergenic ones, as indicated by the black box, and emphasized by red text color. These modifications are also shown in red in (B) and can be seen to be among the top-most marks for variable importance in separation of genic from intergenic regions. UCSC genome browser snapshot of genes (D) TEAD1, (E) CHRM2, and (F) CALD1, showing enrichment of acetylations as compared with neighboring intergenic regions.
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fig4: Acetylations within the gene body distal to exon–intron boundaries and DNAse-I hypersensitive sites in IMR90. (A) ROC curves showing classification of distal genic regions using all 24 modifications (blue) or only 15 acetylations (green). (B) Out-of-bag variable importance of acetylations in classification of distal genic regions against intergenic regions. (C) Heatmap showing enrichment of acetylations in genic regions as compared with intergenic ones using a Z-score normalized measure. Only certain acetylations show enrichment in a majority of genic regions as compared with intergenic ones, as indicated by the black box, and emphasized by red text color. These modifications are also shown in red in (B) and can be seen to be among the top-most marks for variable importance in separation of genic from intergenic regions. UCSC genome browser snapshot of genes (D) TEAD1, (E) CHRM2, and (F) CALD1, showing enrichment of acetylations as compared with neighboring intergenic regions.

Mentions: In both 1H and IMR90, the top two informative marks are H3K36me3 and H3K79me1, which rank well above all other marks (Figure 3, C and D). By AUC analysis, the performance of these two marks alone is equivalent to that of all 24 marks in IMR90 (AUCK36me3,K79me1/AUCall = 100%), although it is somewhat lower in 1H (AUCK36me3,K79me1/AUCall = 96%) (Figure 3, A and B, green). We found that the two marks ranked next that were common to both cell types were H3K27me3 and H3K9me3 (Figure 3, C and D). These modifications may be important because of their relative depletion in genic regions and enrichment in larger intergenic regions (Figure 4D). By including these marks, our classifier achieved almost the same accuracy as all 24 marks in 1H (1H: AUCtop 4/AUCall = 99%) (Figure 3A, magenta vs. blue). Thus, we conclude that the minimal set of modifications required to predict genes within 1% accuracy of the set of all modifications is between 2 and 4, with H3K36me3 and H3K79me1 being the most informative modifications.


Distinct and predictive histone lysine acetylation patterns at promoters, enhancers, and gene bodies.

Rajagopal N, Ernst J, Ray P, Wu J, Zhang M, Kellis M, Ren B - G3 (Bethesda) (2014)

Acetylations within the gene body distal to exon–intron boundaries and DNAse-I hypersensitive sites in IMR90. (A) ROC curves showing classification of distal genic regions using all 24 modifications (blue) or only 15 acetylations (green). (B) Out-of-bag variable importance of acetylations in classification of distal genic regions against intergenic regions. (C) Heatmap showing enrichment of acetylations in genic regions as compared with intergenic ones using a Z-score normalized measure. Only certain acetylations show enrichment in a majority of genic regions as compared with intergenic ones, as indicated by the black box, and emphasized by red text color. These modifications are also shown in red in (B) and can be seen to be among the top-most marks for variable importance in separation of genic from intergenic regions. UCSC genome browser snapshot of genes (D) TEAD1, (E) CHRM2, and (F) CALD1, showing enrichment of acetylations as compared with neighboring intergenic regions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232531&req=5

fig4: Acetylations within the gene body distal to exon–intron boundaries and DNAse-I hypersensitive sites in IMR90. (A) ROC curves showing classification of distal genic regions using all 24 modifications (blue) or only 15 acetylations (green). (B) Out-of-bag variable importance of acetylations in classification of distal genic regions against intergenic regions. (C) Heatmap showing enrichment of acetylations in genic regions as compared with intergenic ones using a Z-score normalized measure. Only certain acetylations show enrichment in a majority of genic regions as compared with intergenic ones, as indicated by the black box, and emphasized by red text color. These modifications are also shown in red in (B) and can be seen to be among the top-most marks for variable importance in separation of genic from intergenic regions. UCSC genome browser snapshot of genes (D) TEAD1, (E) CHRM2, and (F) CALD1, showing enrichment of acetylations as compared with neighboring intergenic regions.
Mentions: In both 1H and IMR90, the top two informative marks are H3K36me3 and H3K79me1, which rank well above all other marks (Figure 3, C and D). By AUC analysis, the performance of these two marks alone is equivalent to that of all 24 marks in IMR90 (AUCK36me3,K79me1/AUCall = 100%), although it is somewhat lower in 1H (AUCK36me3,K79me1/AUCall = 96%) (Figure 3, A and B, green). We found that the two marks ranked next that were common to both cell types were H3K27me3 and H3K9me3 (Figure 3, C and D). These modifications may be important because of their relative depletion in genic regions and enrichment in larger intergenic regions (Figure 4D). By including these marks, our classifier achieved almost the same accuracy as all 24 marks in 1H (1H: AUCtop 4/AUCall = 99%) (Figure 3A, magenta vs. blue). Thus, we conclude that the minimal set of modifications required to predict genes within 1% accuracy of the set of all modifications is between 2 and 4, with H3K36me3 and H3K79me1 being the most informative modifications.

Bottom Line: Unexpectedly, we found that histone acetylation alone performs well in distinguishing these unique genomic regions.Further, we found the association of characteristic acetylation patterns with genic regions and association of chromatin state with splicing.Taken together, our work underscores the diverse functional roles of histone acetylation in gene regulation and provides several testable hypotheses to dissect these roles.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653 Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, California 92037 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.

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Related in: MedlinePlus