Methylation Mesa define functional regulatory elements for targeted gene activation

Year: 2026

Type: article

Abstract: DNA methylation and mRNA expression correlations are often presented with inconsistent evidence supporting causal regulation. We hypothesized that causal regulatory methylation elements would exhibit heightened demethylation sensitivity. To investigate, we analyzed 20 whole genomic bisulfite sequenced samples before and after demethylation and identified narrow width (45 294 bp) elements within a short plateau, termed Methylation Mesa (MM). The Mesa signature was conserved across species and was independent of CpG islands. Mesa also demonstrate high concordance with primed and active histone marks. To assess causality, we developed CRISPR DiR, a highly precise targeted demethylation technology. Targeted demethylation of a Mesa triggers locus and distal chromatin rewiring events that initiate mRNA expression significantly greater than promoter CpG island targeting. Thus, Mesa are self-sustaining epigenetic regulatory elements that maintain long-term gene activation through focused demethylation only within the Mesa core, resulting in subsequent histone modifications and chromatin rewiring events that interact with distal elements also marked as Mesas.

Source: Nature Communications

DOI: 10.1038/s41467-026-76648-4

Authors: Y. V. Liu, J. Suryatenggara, H. Wong, M. K. Jayasinghe, J. P. Tang, H. K. Tan, J. Kwon, Q. Zhou, J. Zhang, S. Moein, S. Ummarino, M. T. N. Le, J. G. Doench, T. Benoukraf, L. Chai, D. Hiwase, D. Thomas, A. Di Ruscio, D. G. Tenen, M. A. Bassal

Institutions: Broad Institute, Cancer Science Institute of Singapore, National University of Singapore, Brigham and Women's Hospital, Harvard University, Harvard Stem Cell Institute, Memorial University of Newfoundland, Royal Adelaide Hospital, South Australian Health and Medical Research Institute, Central Adelaide Local Health Network, The University of Adelaide, Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, Beth Israel Deaconess Medical Center

Language: English

Topic: Epigenetics and DNA Methylation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,990

Funders: U.S. Department of Defense, Bristol-Myers Squibb, National Research Foundation, National Research Foundation Singapore, Canada Research Chairs, Fondazione Cariplo, Ministry of Education, India, Associazione Italiana per la Ricerca sul Cancro, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Medical Research Council, Cancer Science Institute of Singapore, National University of Singapore, National Heart, Lung, and Blood Institute, National Cancer Institute

OpenAlex ID: W7204212274