Biology subjects

Elder, E.

Publications and source records attributed to Elder, E..

3 recordsLinked to original sources

bioRxiv2026

Mouse embryonic stem cells exhibit cancer-like DNA methylation landscapes upon DNMT1 overexpression

DNMT1 overexpression is frequently observed in cancer and other pathologies, yet its direct impact on DNA methylation remains poorly defined. Using whole-genome methyl sequencing, we show that overexpressing DNMT1 in mouse embryonic stem cells (mESCs) induces global hypomethylation, focal hypermethylation in promoters and CpG islands, and increased methylome variability--well-documented characteristics of cancer. We also find that differential promoter methylation is associated with developmental (axon guidance, Wnt) and disease (cancer, cardiomyopathy) pathways and correlates with altered gene expression. Additionally, DNMT3A/B levels are reduced, indicating that excess DNMT1 perturbs the broader DNA methylation machinery. Moreover, to model targeted therapies, we reveal that hypermethylation is mostly erased following DNMT1 depletion, but a substantial portion persists. Hypermethylation is then largely regained upon reinstating DNMT1 overexpression, only achieving permanent erasure at a minority of regions. Finally, promoter hypermethylation detected in mESCs is observed across diverse human cancers, supporting its biological significance and the translational relevance of this study. Overall, these findings illuminate how DNMT1 overexpression disrupts DNA methylation homeostasis, providing mechanistic insight into its pathogenic consequences and therapeutic targeting. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/701550v4_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@437e74org.highwire.dtl.DTLVardef@1232933org.highwire.dtl.DTLVardef@165f5b4org.highwire.dtl.DTLVardef@e619dc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Mouse embryonic stem cells require sustained DNMT1-mediated DNA methylation maintenance for epigenomic, genomic and functional integrity

Epigenetic mechanisms are crucial for developmental programming and can be disrupted by environmental stressors, increasing susceptibility to disease. This has sparked interest in therapies for restoring epigenetic balance, but it remains uncertain whether disordered epigenetic mechanisms can be fully corrected. Disruption of DNA methyltransferase 1 (DNMT1), responsible for DNA methylation maintenance, has particularly devastating biological consequences. Therefore, here we explored if rescuing DNMT1 activity is sufficient to reverse the effects of its loss utilizing mouse embryonic stem cells. However, only partial reversal could be achieved. Extensive changes in DNA methylation, histone modifications and gene expression were detected, along with transposable element de-repression and genomic instability. Reduction of cellular size, complexity and proliferation rate were observed, as well as lasting effects in germ layer lineages and embryoid bodies. Interestingly, by analyzing the impact on imprinted regions, we uncovered 20 regions exhibiting imprinted-like signatures. Notably, while many permanent effects persisted throughout Dnmt1 inactivation and rescue, others arose from the rescue intervention. Lastly, rescuing DNMT1 after differentiation initiation worsened outcomes, reinforcing the need for early intervention. Our findings highlight the far-reaching functions of DNMT1 and provide valuable perspectives on the repercussions of epigenetic perturbations during early development and the challenges of rescue interventions. HIGHLIGHTS- Extensive changes to epigenomic landscapes and gene expression following transient loss of DNMT1 activity - Dysregulation of known imprinted regions and identification of 20 regions with imprinted-like signatures - De-repression of MERVL and MT2 LTRs with evidence of chimeric gene transcript generation - Shorter telomeres, DNA damage accumulation and reduction of cell size, internal complexity and proliferation rate - Lasting effects upon differentiation toward germ layer lineages and embryoid bodies - Worsened molecular and cellular outcomes when delaying Dnmt1 rescue until after differentiation initiation O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/592204v3_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@d88ea7org.highwire.dtl.DTLVardef@17d7c87org.highwire.dtl.DTLVardef@17ab304org.highwire.dtl.DTLVardef@7ef981_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

cell biology↗

bioRxiv2021

Opsonization by non-neutralizing antibodies can confer protection to SARS-CoV-2 despite Spike-dependent modulation of phagocytosis

Spike-specific antibodies are central to effective COVID19 immunity. Research efforts have focused on antibodies that neutralize the ACE2-Spike interaction but not on non-neutralizing antibodies. Antibody-dependent phagocytosis is an immune mechanism enhanced by opsonization, where typically, more bound antibodies trigger a stronger phagocyte response. Here, we show that Spike-specific antibodies, dependent on concentration, can either enhance or reduce Spike-bead phagocytosis by monocytes independently of the antibody neutralization potential. Surprisingly, we find that both convalescent patient plasma and patient-derived monoclonal antibodies lead to maximum opsonization already at low levels of bound antibodies and is reduced as antibody binding to Spike protein increases. Moreover, we show that this Spike-dependent modulation of opsonization seems to affect the outcome in an experimental SARS-CoV-2 infection model. These results suggest that the levels of anti-Spike antibodies could influence monocyte-mediated immune functions and propose that non-neutralizing antibodies could confer protection to SARS-CoV-2 infection by mediating phago-cytosis.

immunology↗