A chromatin- linked CPL2-PHD2/3 module sustains multiple DNA methylation pathways and Polycomb silencing

• 成果类型: Article
• 署名作者: Zhang, Lingrui; Tang, Kai; Long, Tiandan; Zhang, Li-Li; Zhu, Peipei; Fan, Fuhua; Fu, Jianxin; Zhang, Chao; Zhu, Jian-Kang
• 署名单位: Purdue University System; Purdue University; Sichuan Agricultural University; Purdue University System; Purdue University; Guizhou University; Zhejiang A&F University; Southern University of Science & Technology; Southern University of Science & Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2523102122
• 发表日期: 2025-11-25
• 页码: e2523102122
• 关键词: dna methylation; epigenetics; gene silencing; histone modification; polycomb; FLOWERING-LOCUS-T; HETEROCHROMATIN PROTEIN1; ARABIDOPSIS HOMOLOG; maintenance; methyltransferase; transcription; mechanisms; TFL2/LHP1; occupancy; genome

摘要

While multiple chromatin-based epigenetic pathways are well characterized, their genome-wide coordination and hierarchical interplay remain poorly understood. We previously identified the BAH-PHD-CPL2 complex, where AIPP3 binds H3K27me3 via its BAH domain and, in concert with PHD2 and PHD3 (PHD2/3), recruits CPL2 to repress transcription by dephosphorylating RNA Polymerase II. Here, we show that CPL2 and PHD2/3 form a distinct module (CPL2-PHD2/3) that safeguards CHH DNA methylation and silences CHH-methylated sites at transposable elements (TEs) through engagement of multiple DNA methylation pathways. The CPL2-PHD2/3 module physically associates with SUVH4 and SUVH5 (SUVH4/5) to preserve SUVH4/5-CMT2-mediated CHH methylation at a subset of H3K9me2-marked regions. Chromatin enrichment of PHD3 likewise enables the module to sustain RNA-directed DNA methylation (RdDM)-mediated CHH DNA methylation at sites bearing H3K9me2, H3K27me3, or neither. Thus, CPL2-PHD2/3 emerges as a previously underappreciated, multifunctional regulator of plant DNA methylation networks. Unexpectedly, its gene repression function is uncoupled from DNA methylation. CPL2-PHD2/3 represses Polycomb-marked genes by interacting with LHP1 or recognizing hypomethylated H3K4. While it cooperates with LHP1 at a subset of targets, it also independently silences many more genes that LHP1 alone cannot repress, both sets of genes being critical for proper development. This dual, yet largely LHP1-insufficient, repression mode singles out CPL2-PHD2/3 as the essential executor of Polycomb silencing. Together, our findings establish CPL2-PHD2/3 as a chromatin-responsive integrator that spans DNA methylation and Polycomb-associated repression, providing a unifying mechanism for epigenetic control of both TEs and genes across diverse chromatin landscapes. Significance Epigenetic silencing in plants involves diverse pathways, but how they are integrated into a coherent repression system remains obscure. We reveal the CPL2-PHD2/3 module as a chromatin- responsive hub that preserves CHH methylation through both the de novo RdDM route and the SUVH4/5-CMT2 maintenance loop, while also enforcing Polycomb-associated silencing through cooperating with LHP1 or fulfilling repression unmet by LHP1 alone. By channeling DNA methylation and Polycomb cues into a single silencing output, this multifaceted integrator suggests a higher-order principle by which seemingly disparate epigenetic circuits converge to sustain genome integrity and developmental precision.