Comprehensive Analysis of H3K27me3 LOCKs Under Different DNA Methylation Contexts Reveal Epigenetic Redistribution in Tumorigenesis

Overview

Journal Epigenetics Chromatin

Publisher Biomed Central

Date 2025 Jan 20

PMID 39833880

Authors

Yuan Liang

Mengni Liu

Bingyuan Liu

Benjamin Ziman

Guanjie Peng

Qiong Mao

Xingzhe Wang

Lizhen Jiang

De-Chen Lin

Yueyuan Zheng

Affiliations

Soon will be listed here.

Abstract

Background: Histone modification H3K27me3 plays a critical role in normal development and is associated with various diseases, including cancer. This modification forms large chromatin domains, known as Large Organized Chromatin Lysine Domains (LOCKs), which span several hundred kilobases.

Result: In this study, we identify and categorize H3K27me3 LOCKs in 109 normal human samples, distinguishing between long and short LOCKs. Our findings reveal that long LOCKs are predominantly associated with developmental processes, while short LOCKs are enriched in poised promoters and are most associated with low gene expression. Further analysis of LOCKs in different DNA methylation contexts shows that long LOCKs are primarily located in partially methylated domains (PMDs), particularly in short-PMDs, where they are most likely responsible for the low expressions of oncogenes. We observe that in cancer cell lines, including those from esophageal and breast cancer, long LOCKs shift from short-PMDs to intermediate-PMDs and long-PMDs. Notably, a significant subset of tumor-associated long LOCKs in intermediate- and long-PMDs exhibit reduced H3K9me3 levels, suggesting that H3K27me3 compensates for the loss of H3K9me3 in tumors. Additionally, we find that genes upregulated in tumors following the loss of short LOCKs are typically poised promoter genes in normal cells, and their transcription is regulated by the ETS1 transcription factor.

Conclusion: These results provide new insights into the role of H3K27me3 LOCKs in cancer and underscore their potential impact on epigenetic regulation and disease mechanisms.

References

Frankish A, Diekhans M, Jungreis I, Lagarde J, Loveland J, Mudge J . GENCODE 2021. Nucleic Acids Res. 2020; 49(D1):D916-D923. PMC: 7778937. DOI: 10.1093/nar/gkaa1087. View

Wu M, Tsai T, Beaudet A . Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain. Genes Dev. 2006; 20(20):2859-70. PMC: 1619944. DOI: 10.1101/gad.1452206. View

Kim D, Paggi J, Park C, Bennett C, Salzberg S . Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019; 37(8):907-915. PMC: 7605509. DOI: 10.1038/s41587-019-0201-4. View

Bernstein B, Mikkelsen T, Xie X, Kamal M, Huebert D, Cuff J . A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006; 125(2):315-26. DOI: 10.1016/j.cell.2006.02.041. View

Feinberg A, Vogelstein B . Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983; 301(5895):89-92. DOI: 10.1038/301089a0. View

Yuan J, Jiang Q, Gong T, Fan D, Zhang J, Chen F . Loss of grand histone H3 lysine 27 trimethylation domains mediated transcriptional activation in esophageal squamous cell carcinoma. NPJ Genom Med. 2021; 6(1):65. PMC: 8358006. DOI: 10.1038/s41525-021-00232-6. View

Wen B, Wu H, Shinkai Y, Irizarry R, Feinberg A . Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet. 2009; 41(2):246-50. PMC: 2632725. DOI: 10.1038/ng.297. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Fernandes J, Zamudio-Hurtado A, Clawson H, Kent W, Haussler D, Salama S . The UCSC repeat browser allows discovery and visualization of evolutionary conflict across repeat families. Mob DNA. 2020; 11:13. PMC: 7110667. DOI: 10.1186/s13100-020-00208-w. View

10.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

11.

Hovestadt V, Jones D, Picelli S, Wang W, Kool M, Northcott P . Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature. 2014; 510(7506):537-41. DOI: 10.1038/nature13268. View

12.

Deblois G, Madani Tonekaboni S, Grillo G, Martinez C, Kao Y, Tai F . Epigenetic Switch-Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer. Cancer Discov. 2020; 10(9):1312-1329. DOI: 10.1158/2159-8290.CD-19-1493. View

13.

Bieluszewski T, Xiao J, Yang Y, Wagner D . PRC2 activity, recruitment, and silencing: a comparative perspective. Trends Plant Sci. 2021; 26(11):1186-1198. DOI: 10.1016/j.tplants.2021.06.006. View

14.

Sanchez-Danes A, Blanpain C . Deciphering the cells of origin of squamous cell carcinomas. Nat Rev Cancer. 2018; 18(9):549-561. PMC: 7170720. DOI: 10.1038/s41568-018-0024-5. View

15.

Nassar L, Barber G, Benet-Pages A, Casper J, Clawson H, Diekhans M . The UCSC Genome Browser database: 2023 update. Nucleic Acids Res. 2022; 51(D1):D1188-D1195. PMC: 9825520. DOI: 10.1093/nar/gkac1072. View

16.

Gao B, Huang Q, Baudis M . segment_liftover : a Python tool to convert segments between genome assemblies. F1000Res. 2018; 7:319. PMC: 5998006. DOI: 10.12688/f1000research.14148.2. View

17.

Kent W, Zweig A, Barber G, Hinrichs A, Karolchik D . BigWig and BigBed: enabling browsing of large distributed datasets. Bioinformatics. 2010; 26(17):2204-7. PMC: 2922891. DOI: 10.1093/bioinformatics/btq351. View

18.

Kumar D, Cinghu S, Oldfield A, Yang P, Jothi R . Decoding the function of bivalent chromatin in development and cancer. Genome Res. 2021; 31(12):2170-2184. PMC: 8647824. DOI: 10.1101/gr.275736.121. View

19.

Johnstone S, Gladyshev V, Aryee M, Bernstein B . Epigenetic clocks, aging, and cancer. Science. 2022; 378(6626):1276-1277. DOI: 10.1126/science.abn4009. View

20.

Ziman B, Yang Q, Zheng Y, Sheth M, Nam C, Zhao H . Epigenomic analyses identify FOXM1 as a key regulator of anti-tumor immune response in esophageal adenocarcinoma. Cell Death Dis. 2024; 15(2):152. PMC: 10876663. DOI: 10.1038/s41419-024-06488-x. View