Biology subjects

Angel, J. C.

Publications and source records attributed to Angel, J. C..

3 recordsLinked to original sources

bioRxiv2026

Flanking DNA sequences determine DNA methylation maintenance in proliferation, cancer and aging

DNA methylation is a stable epigenetic modification essential for promoter silencing, retrotransposon silencing, genomic imprinting, and X-chromosome inactivation. Symmetrical DNA methylation at CpG dinucleotides is maintained after every round of cell division by the DNMT1-UHRF1 maintenance methyltransferase complex. Here we define a conserved rank order of DNA hexanucleotide sequences surrounding CpG sites that determines baseline DNA methylation levels in cells and the probability that DNA methylation is retained across cell divisions. This rank order is conserved in vertebrates and does not depend on TET enzymatic activity. CpG sites in hexanucleotide sequences less favored by DNMT1 are more susceptible to replication-dependent loss of DNA methylation over time; consequently, the methylation status of these motifs serves as a marker of cumulative cell divisions, biological age and cancer progression. Thus, the intrinsic vulnerability stemming from the sequence preference of the DNMT1-UHRF1 complex compromises the long-term stability of DNA methylation, especially at heterochromatic sites in proliferating cells, and contributes to the epigenetic dysregulation observed in cancer and aging.

genomics↗

bioRxiv2025

Crosstalk between the Methyl-Cytosine Dioxygenase TET3 and the Methyl-CpG-binding protein MECP2 Controls Neuronal Maturation

Active DNA demethylation depends on Ten-Eleven-Translocation (TET) enzymes, which oxidize 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC) and further derivatives. Mutations in TET3, encoding the predominant neuronal isoform, lead to Beck-Fahrner syndrome, a neurodevelopmental disorder. Using human iPSC-derived neurons, we show that TET3 is dispensable for neuronal specification but critical for subsequent maturation. Differentiating TET3-deficient neurons exhibit delayed transcriptional and proteomic transitions, altered synaptic signatures, and impaired network activity, indicating delayed functional maturation. Mechanistically, we identified an interaction between TET3 and the mC/hmC-binding protein MECP2, pathogenic variants of which cause Rett syndrome. MECP2 negatively regulates TET3 activity, as demonstrated in functional assays and by inverse hmC patterns in MECP2- and TET3-deficient neurons. Despite this, MECP2- and TET3-deficient neurons exhibit highly similar phenotypes later in differentiation. Our findings uncover a functional interplay between TET3 and MECP2 that coordinates DNA methylation and chromatin dynamics during neuronal maturation, suggesting a shared pathogenic mechanism in Beck-Fahrner and Rett syndromes.

neuroscience↗

bioRxiv2024

OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide

The O-GlcNAc transferase OGT interacts robustly with all three mammalian TET methylcytosine dioxygenases. We show here that deletion of the Ogt gene in mouse embryonic stem cells (mESC) results in a widespread increase in the TET product 5-hydroxymethylcytosine (5hmC) in both euchromatic and heterochromatic compartments, with concomitant reduction of the TET substrate 5-methylcytosine (5mC) at the same genomic regions. mESC engineered to abolish the TET1-OGT interaction likewise displayed a genome-wide decrease of 5mC. DNA hypomethylation in OGT-deficient cells was accompanied by de-repression of transposable elements (TEs) predominantly located in heterochromatin, and this increase in TE expression was sometimes accompanied by increased cis-expression of genes and exons located 3 of the expressed TE. Thus, the TET-OGT interaction prevents DNA demethylation and TE expression in heterochromatin by restraining TET activity genome-wide. We suggest that OGT protects the genome against DNA hypomethylation and impaired heterochromatin integrity, preventing the aberrant increase in TE expression observed in cancer, autoimmune-inflammatory diseases, cellular senescence and ageing.

molecular biology↗