Biology subjects

Lopez-Moyado, I. F.

Publications and source records attributed to Lopez-Moyado, I. F..

3 recordsLinked to original sources

bioRxiv2026

TET loss of function selects for aneuploidies that confer a proliferative advantage

Mutations in the Ten-Eleven Translocation (TET) family of DNA dioxygenases are among the most common epigenetic alterations in clonal hematopoiesis and hematologic malignancies, yet how TET loss of function reshapes genome evolution during cellular expansion remains to be fully understood. Here we show that loss of Tet2/3 in invariant natural killer T (iNKT) cells drives aggressive lymphoid expansion that is consistently associated with recurrent chromosome 17 trisomy, a dominant aneuploid state observed across more than ten independently derived tumors following transplantation into immunocompetent recipient mice. Single-cell whole-genome sequencing of TET-deficient iNKT cells induced to proliferate in culture with antigen and IL-2 stimulation revealed that rare pre-existing cells with chromosome 17 trisomy appeared soon after Tet gene deletion in the thymus, together with cells harboring other copy number alterations, but only the cells with chromosome 17 trisomy were progressively enriched during further expansion. Similarly, inducibly Tet-deficient mouse embryonic stem cells (mESCs) showed selection for aneuploid states that were present prior to Tet gene deletion, including trisomy of chromosome 6. Reanalysis of independent datasets from Dnmt3a-deficient mouse lymphomas identified recurrent chromosome gains, including chromosome 17 trisomy. Our results establish TET and DNMT3A deficiency as drivers of karyotypic evolution, and suggest that disruption of DNA methylation/ demethylation pathways through either TET or DNMT3A deletion promotes chromosomal instability, in part by facilitating the emergence and selection of cryptic aneuploid subclones during clonal expansion.

genetics↗

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

Loss of TET function in T regulatory cells yields ex-Treg cells biased toward T follicular helper cells, causingautoimmune diseases through autoantibody production

T regulatory cells (Treg cells) express the transcription factor FOXP3 and maintain immune homeostasis by attenuating effector responses. Treg cells are prone to lose FOXP3 and convert to pathological ex-Treg cells under conditions of strong or chronic inflammation. One mechanism for loss of FOXP3 expression involves increased DNA methylation of intronic enhancers CNS1 and CNS2 in the Foxp3 locus; these enhancers are maintained in a demethylated state by TET enzymes, 5-methylcytosine (5mC) dioxygenases that generate 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines that are essential intermediates in all pathways of DNA demethylation. We previously showed that FOXP3+ Treg cells from Tet2/3-deficient (Tet2/3 DKO) mice displayed increased methylation of CNS1 and CNS2 and converted to FOXP3-negative ex-Treg cells considerably more efficiently than WT Treg cells. Here we extend our previous analysis of Foxp3-Cre Tet2/3fl/fl mice. We classified the mice as DKO- moderate or DKO-severe based on the total number of leukocytes in the spleen and peripheral lymph nodes and investigated the phenotypic and molecular basis for the progressive inflammation occurring in these mice. RNA-seq as well as histological and immunocytochemical analyses showed a striking expansion of T follicular helper (Tfh) cells and plasma cells in Tet2/3 DKO-severe mice. RNA-seq analyses also revealed increased induction of interferon-stimulated genes (ISGs) in CD4+ FOXP3- T cells from these mice, and single-cell (sc) RNA-seq analyses suggested strongly that this was due to skewed differentiation of both Tet2/3 DKO FOXP3+ Treg cells and Tet2/3 DKO FOXP3- ex-Treg cells into Tfh-like cells. Base-resolution "6-base" sequencing showed the expected loss of 5hmC and increased 5mC in Tfh cells purified from Tet2/3 DKO-severe mice, and suggested that the observed bias in gene expression patterns could arise both from a direct increase in methylation of essential enhancers stemming from TET deficiency, or because methylation interfered with binding of methylation-sensitive transcriptional regulators including CTCF.

immunology↗