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. 2021 Jan 15;12(1):400.
doi: 10.1038/s41467-020-20492-7.

"VSports手机版" Cellular Heterogeneity-Adjusted cLonal Methylation (CHALM) improves prediction of gene expression

Jianfeng Xu #  1   2 , Jiejun Shi #  1 , Xiaodong Cui  2 , Ya Cui  1 , Jingyi Jessica Li  3 , Ajay Goel  4 , Xi Chen  2 , Jean-Pierre Issa  5 , Jianzhong Su  6 , Wei Li  7
Affiliations

Cellular Heterogeneity-Adjusted cLonal Methylation (CHALM) improves prediction of gene expression

Jianfeng Xu (VSports app下载) et al. Nat Commun. .

Abstract

Promoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak VSports手机版. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a methylation quantification method. CHALM improves understanding of the functional consequences of DNA methylation, including its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method enables detection of differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms. .

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Conflict of interest statement (V体育ios版)

After completing the current studies at Baylor College of Medicine, J. X. became a full-time employee at Helio Health. W V体育安卓版. L. is a consultant for Helio Health and ChosenMed. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. CHALM quantifies cell heterogeneity–adjusted DNA methylation level.
a, b show two different methylation patterns of a promoter region that cannot be distinguished by the traditional method. c Scatter plot shows a comparison of the methylation level calculated by the traditional and CHALM methods for the promoter CGIs of CD3 primary cells.
Fig. 2
Fig. 2. The CHALM method better predicts gene expression.
a Scatter plots show the correlation between gene expression and methylation level calculated using both methods. Balanced promoter CGIs (Methods section) of CD3 primary cells are used. Each data point represents the average value of 10 promoter CGIs, and the Spearman correlation is calculated based on original data for each promoter CGI. Comparison of correlation (between the traditional method and CHALM) P values calculated by permutation (Methods section): <1 × 10−4. b Similar to a but focusing on low-methylation genes. Comparison of correlation permutation P values: <1 × 10−4. c Scatter plots show the correlation between H3K4me3 ChIP-seq intensity and methylation level calculated by the traditional and CHALM methods. Balanced promoter CGIs are used. Comparison of correlation permutation P values: <1 ×  10−4. d Similar to c but focusing on low-methylation genes. Comparison of correlation permutation P values: <1 × 10−4. e, f Methylation status of reads mapped to the promoter CGI of HIST2H2BF or SSTR5, respectively. Black circles: mCpG; white circles: CpG.
Fig. 3
Fig. 3. Clonal information is crucial for gene expression prediction.
a Prediction of gene expression based on raw bisulfite sequencing reads via a deep-learning framework. b Disruption of read clonal information by shuffling the mCpGs among mapped reads. c The clonal information is disrupted before prediction. Comparison of correlation (between prediction models with and without clonal information disrupted) permutation P values: <1 × 10−4.
Fig. 4
Fig. 4. CHALM better identifies hypermethylated promoter CGIs during tumorigenesis.
a Scatter plots show the correlation between differential expression and differential methylation calculated by the traditional and CHALM methods. All promoter CGIs were included for analysis, but only those exhibiting a significant methylation change between normal and cancerous lung tissue were plotted. X-axis: differential methylation ratio; y-axis: differential expression (log2FoldChange). Comparison of correlation (between the traditional method and CHALM) permutation P values: <1 × 10−4. b A large fraction of hypermethylated promoter CGIs identified by the traditional method can be recovered using the CHALM method, as indicated by the Venn diagram. Bar plot shows enrichment of the H3K27me3 peak in three different gene sets.
Fig. 5
Fig. 5. CHALM provides better identification of functionally related DMRs.
a KEGG pathway enrichment of the top 2000 hypomethylated DMRs in SCLC. ‘q-value’ refers to one-sided Fisher’s Exact test P value adjusted by Benjamini–Hochberg procedure. b Expression change of genes with hypomethylated DMRs in the KEGG pathways shown in a between LUAD (79) and SCLC (79) patients. The left-to-right order is the same as the top-to-right order shown in a. Two-sided one-sample t-test is used. Sample sizes from left to right for test are 57, 41,24, 30, and 49, respectively. c Expression of SSTR1 in LUAD (79) and SCLC (79) patients. Two-sided Wald test P value is adjusted by Benjamini–Hochberg procedure. d Methylation status of reads mapped to the CHALM-unique hypomethylated DMR found in the SSTR1 promoter region. Only 50 reads are selected for visualization. The methylation levels shown were calculated based on the original dataset. Black circles: mCpG; white circles: CpG. Boxplot definition: line in the box center refers to the median, the limits of box refer to the 25th and 75th percentiles and whiskers are plotted at the highest and lowest points within the 1.5 times interquartile range.
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