Biology subjects

Wiseman, A. K.

Publications and source records attributed to Wiseman, A. K..

4 recordsLinked to original sources

bioRxiv2026

A feed-forward UHRF1 read-write mechanism supports H3 multi- mono-ubiquitination and DNA methylation maintenance at CpG-sparse regions

The epigenetic inheritance of mammalian DNA methylation requires DNMT1 and its E3 ligase cofactor UHRF1. At newly replicated chromatin, UHRF1 recognition of hemi-methylated DNA and histone H3 N-terminal tails directs catalysis of H3K14, H3K18, and/or H3K23 mono-ubiquitination to recruit DNMT1. While it is appreciated that UHRF1 can deposit multiple mono-ubiquitin marks on a single H3 tail and that DNMT1 recognizes this state through tandem ubiquitin interacting motifs, the mechanism that promotes successive ubiquitination and the biological function of multi-mono-ubiquitination are unknown. Here, we show that UHRF1 directly binds its mono-ubiquitinated H3 products through a previously uncharacterized LGDDSL loop in Tudor 2 of its tandem Tudor domain (TTD) to promote further ubiquitin deposition. Disruption of this ubiquitin reading activity impairs H3 multi-mono-ubiquitination and accelerates DNA methylation loss within late-replicating, CpG-sparse genomic regions that are characteristic of partially methylated domains (PMDs) in cancer and aging cells. These methylation defects overlap those observed by disruption of UHRF1 ubiquitin ligase activity, providing convergent evidence that both writing and reading of H3 ubiquitination support CpG-sparse DNA methylation maintenance. Together, these findings establish a feed-forward ubiquitin read-write mechanism that generates multi-mono-ubiquitinated H3 and safeguards DNMT1-dependent DNA methylation maintenance at vulnerable genomic regions of the mammalian methylome.

molecular biology↗

bioRxiv2025

Dual EZH1/2 inhibition enhances DNMT inhibitor efficacy in colon cancer through targeting H3K27me1

Abnormal DNA methylation patterning is a defining epigenetic hallmark of human cancer and is therapeutically targetable with DNA methyltransferase inhibitors (DNMTis). However, DNMTi-induced DNA hypomethylation promotes adaptive chromatin remodeling that limits molecular and therapeutic responses to these drugs. Here, we identify EZH1-dependent H3K27 mono-methylation (H3K27me1) as a previously unrecognized adaptive barrier to DNMTi response in colorectal cancer. While EZH2-selective inhibitors deplete H3K27me2 and H3K27me3, they preserve EZH1-dependent H3K27me1 at Polycomb-enriched genomic regions. In contrast, dual EZH1/2 inhibition eliminates all H3K27 methylation states and robustly synergizes with DNMTi to enhance transcriptional activation and growth suppression. Mechanistically, dual EZH1/2 inhibition induces a redistribution of p300/CBP-dependent H3K27 acetylation (H3K27ac), generating a therapy-associated bivalent chromatin state characterized by coexisting DNA methylation and H3K27ac. DNMT inhibition resolves this induced bivalency, enabling activation of tumor-suppressive transcriptional programs. At the same time, coordinated loss of H3K27me1 and gene-body DNA methylation, together with depletion of promoter-associated H3K27ac, suppresses MYC- and E2F-driven oncogenic transcription networks that define the cancer cell-intrinsic therapeutic response. Collectively, these findings establish EZH1-dependent H3K27me1 as a key mediator of adaptive epigenetic plasticity and provide mechanistic rationale for combining DNMT inhibitors with dual EZH1/2i inhibitors to reprogram chromatin and suppress oncogenic transcription in solid tumors. HighlightsO_LIEZH1-dependent H3K27me1 sustains an adaptive barrier to DNMT inhibitor response in colorectal cancer. C_LIO_LIDual EZH1/2 inhibition eliminates all H3K27 methylation states and remodels chromatin architecture. C_LIO_LIEZH inhibition induces a DNA methylation-H3K27ac bivalent chromatin state. C_LIO_LIDNMT and EZH1/2 co-inhibition reprograms enhancers and promoters to activate tumor-suppressive pathways. C_LIO_LICombination therapy suppresses MYC/E2F-driven oncogenic transcription, defining its cancer cell-intrinsic therapeutic efficacy. C_LI

cancer biology↗

bioRxiv2024

UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation

The RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. Nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). Here, we profile contributions of UHRF1 and DNMT1 to genome-wide DNA methylation inheritance and dissect specific roles for ubiquitin signaling in this process. We reveal DNA methylation maintenance at low-density CpGs is vulnerable to disruption of UHRF1 ubiquitin ligase activity and DNMT1 ubiquitin reading activity through UIM1. Hypomethylation of low-density CpGs in this manner induces formation of partially methylated domains (PMD), a methylation signature observed across human cancers. Furthermore, disrupting DNMT1 UIM2 function abolishes DNA methylation maintenance. Collectively, we show DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.

genomics↗

bioRxiv2022

DNA Methylation Dynamics and Dysregulation Delineated by High-Throughput Profiling in the Mouse

We have developed a mouse Infinium DNA methylation array that contains 297,415 probes to capture the diversity of mouse DNA methylation biology. We present a mouse DNA methylation atlas as a rich reference resource of 1,239 DNA samples encompassing distinct tissues, strains, age, sex, and pathologies. We describe applications for comparative epigenomics, genomic imprinting, epigenetic inhibitors, PDX assessment, backcross tracing, and epigenetic clocks. We dissect DNA methylation processes associated with differentiation, aging and tumorigenesis. Notably, we find that tissue-specific methylation signatures localize to binding sites for transcription factors controlling the corresponding tissue development. Age-associated hypermethylation is enriched at regions of Polycomb repression, while hypomethylation is enhanced at regions bound by cohesin complex members. ApcMin/+ polyp-associated hypermethylation affects enhancers regulating intestinal differentiation, while hypomethylation targets AP-1 binding sites. This MM285 mouse array is widely accessible to the research community, and will accelerate future high sample-throughput studies in this important model organism.

genomics↗