journal contribution posted on 2023-03-31, 00:46 authored by Byungho Lim, Jihyeob Mun, Yong Sung Kim, Seon-Young Kim
Supplementary Figure S1 shows the distribution of chromatin features around mutations across multiple cancer types. Sup S2 and S3 shows the average signal distributions of nucleosome occupancy across several cancer types. Sup S4 shows correlation between histone modifications and mutation rates of indels and SNVs. Sup S5 shows mutation rates in intragenic enhancer relative to non-enhancer Sup S6 shows the relative cumulative frequencies of missense and silent SNVs. Sup S7, S8, S9, S10 shows counts of each of the four indel types across multiple cancer types. Sup S11 shows the average signal distributions of DNA methylation around mutation positions. Sup S12, S13, S14, S15 shows the average signal distribution of a few histone marks and nucleosomes around SNV and indel positions in several tumor types. Sup S16 shows the binding pattern of NER machineries around mutation positions. Sup S17 shows the average distribution of H3K3me3, XPB, and XPD around indel positions from STAD. Sup S18 shows the average distributions of CSB and Pol II around a few TFBS. Sup S19 shows NER activity around mutations. Sup S20 shows relationship between mutation acquisition and chromatin features in MMR- and POLE-deficient tumors. Sup S21 summarizes epigenomic features that distinguish SNVs, indels, and non-mutated positions. Sup S22 shows the signal intensity of TC-NER on 12 types of missense SNVs
Ministry of Science, ICT, and Future Planning
KRIBB Research Initiative
ARTICLE ABSTRACTDynamic chromatin structures result in differential chemical reactivity to mutational processes throughout the genome. To identify chromatin features responsible for mutagenesis, we compared chromatin architecture around single-nucleotide variants (SNV), insertion/deletions (indels), and their context-matched, nonmutated positions. We found epigenetic differences between genomic regions containing missense SNVs and those containing frameshift indels across multiple cancer types. Levels of active histone marks were higher around frameshift indels than around missense SNV, whereas repressive histone marks exhibited the reverse trend. Accumulation of repressive histone marks and nucleosomes distinguished mutated positions (both SNV and indels) from the context-matched, nonmutated positions, whereas active marks were associated with substitution- and cancer type–specific mutagenesis. We also explained mutagenesis based on genome maintenance mechanisms, including nucleotide excision repair (NER), mismatch repair (MMR), and DNA polymerase epsilon (POLE). Regional NER variation correlated strongly with chromatin features; NER machineries exhibited shifted or depleted binding around SNV, resulting in decreased NER at mutation positions, especially at sites of recurrent mutations. MMR-deficient tumors selectively acquired SNV in regions with high active histone marks, especially H3K36me3, whereas POLE-deficient tumors selectively acquired indels and SNV in regions with low active histone marks. These findings demonstrate the importance of fine-scaled chromatin structures and associated DNA repair mechanisms in mutagenesis. Cancer Res; 77(11); 2822–33. ©2017 AACR.