Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells DOI Open Access
Kosuke Yamaguchi, Xiaoying Chen,

Brianna Rodgers

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 11, 2023

Abstract DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It yet unclear if UHRF1 functions solely by stimulating DNMT1, or it has important additional functions. Using degron alleles, we show that depletion causes a much greater loss of than DNMT1 depletion. This not caused passive demethylation as UHRF1-depleted cells proliferate more slowly DNMT1-depleted cells. Instead, bioinformatics, proteomics genetics experiments establish UHRF1, besides activating interacts with DNMT3A DNMT3B promotes their activity. In addition, antagonizes active TET2. Therefore, non-canonical roles contribute importantly to homeostasis; these findings have practical implications for epigenetics health disease.

Language: Английский

The role of aberrant DNA methylation in cancer initiation and clinical impacts DOI Creative Commons
Franziska Geissler, Ksenija Nesic, Olga Kondrashova

et al.

Therapeutic Advances in Medical Oncology, Journal Year: 2024, Volume and Issue: 16

Published: Jan. 1, 2024

Epigenetic alterations, including aberrant DNA methylation, are now recognized as bone fide hallmarks of cancer, which can contribute to cancer initiation, progression, therapy responses and resistance. Methylation gene promoters have a range impacts on risk, clinical stratification therapeutic outcomes. We provide several important examples genes, be silenced or activated by promoter methylation highlight their implications. These include the mismatch repair genes MLH1 MSH2, homologous recombination BRCA1 RAD51C, TERT oncogene within P15/P16/RB1/E2F tumour suppressor axis. also discuss how these changes might occur in first place – whether context CpG island methylator phenotype constitutional methylation. The choice assay used measure significant impact interpretation states, some where this influence decision-making presented. Aberrant patterns circulating (ctDNA) showing great promise non-invasive detection monitoring using liquid biopsies; however, caution must taken interpreting results cases may present. Thus, review aims researchers clinicians with comprehensive summary broad, but subject, illustrating potentials pitfalls assessing cancer.

Language: Английский

Citations

20
Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells DOI Creative Commons
Kosuke Yamaguchi, Xiaoying Chen,

Brianna Rodgers

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 5, 2024

Abstract DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It yet unclear if UHRF1 functions solely by stimulating DNMT1, or it has important additional functions. Using degron alleles, we show that depletion causes a much greater loss of than DNMT1 depletion. This not caused passive demethylation as UHRF1-depleted cells proliferate more slowly DNMT1-depleted cells. Instead, bioinformatics, proteomics genetics experiments establish UHRF1, besides activating interacts with DNMT3A DNMT3B promotes their activity. In addition, antagonizes active TET2. Therefore, non-canonical roles contribute importantly to homeostasis; these findings have practical implications for epigenetics health disease.

Language: Английский

Citations

11
A CRISPR-Cas9 screen reveals genetic determinants of the cellular response to decitabine DOI Creative Commons
Pinqi Zhang, Zhuqiang Zhang, Yaobing Wang

et al.

EMBO Reports, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Abstract Decitabine (DAC), a well-recognized DNA hypomethylating agent, has been applied to treat acute myeloid leukemia. However, clinic investigations revealed that methylation reduction does not correlate with clinical response, and relapse is prevalent. To gain better understanding of its anti-tumor mechanism, we perform temporally resolved CRISPR-Cas9 screen identify factors governing the DAC response. We show damage generated by DNMT-DNA adducts 5-aza-dUTP misincorporation through dCMP deaminase DCTD act as drivers DAC-induced cytotoxicity. The arises during next S phase dependent on replication, unveiling trans-cell cycle effect genome stability. By exploring candidates for synthetic lethality, unexpectedly uncover KDM1A promotes survival after treatment interactions ZMYM3 CoREST, independent demethylase activity or regulation viral mimicry. These findings emphasize importance repair pathways in response provide potential biomarkers.

Language: Английский

Citations

1
Dux cluster duplication ensures full activation of totipotent genes DOI Creative Commons
Meiqi Lin,

Zeling Du,

Dan Guo

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(10)

Published: March 6, 2025

Zygotic genome activation (ZGA) confers to the mouse two-cell (2C) embryo a unique transcriptional profile characterized by transient up-regulation of many totipotency-related genes and MERVL retrotransposons. Intriguingly, those are duplicated clustered in during evolution, including Dux cluster, Obox, Zscan4 family members mice. However, contribution biological significance gene duplication events early development remain poorly understood. Here, we focus on master regulator ZGA that is necessary sufficient for induction 2C-like cells embryonic stem (mESCs). By reducing copies from 31 0 or 1 through CRISPR-Cas9 technology, generate Dux-KO (n = 1) mESC lines, respectively. We uncover awakened much lesser extent mESCs compared wild type following global DNA demethylation reprogramming damage, mimicking intrinsic preimplantation development. Together, cluster critically required full transcripts.

Language: Английский

Citations

1
TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells DOI
Tingting Hong, Jia Li, Lei Guo

et al.

Nature Aging, Journal Year: 2023, Volume and Issue: 3(11), P. 1387 - 1400

Published: Oct. 26, 2023

Language: Английский

Citations

15
Perturbing TET2 condensation promotes aberrant genome-wide DNA methylation and curtails leukaemia cell growth DOI
Lei Guo, Tingting Hong, Yi‐Tsang Lee

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(12), P. 2154 - 2167

Published: Sept. 9, 2024

Language: Английский

Citations

5
KMT2A degradation is observed in decitabine‐responsive acute lymphoblastic leukemia cells DOI Creative Commons

Luisa Brock,

Lina Benzien,

Sandra Lange

et al.

Molecular Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Hypermethylation of tumor suppressor genes is a hallmark leukemia. The hypomethylating agent decitabine covalently binds, and degrades DNA (cytosine‐5)‐methyltransferase 1 (DNMT1). Structural similarities within DNA‐binding domains DNMT1, the leukemic driver histone‐lysine N ‐methyltransferase 2A (KMT2A) suggest that might also affect latter. In acute lymphoblastic leukemia (ALL) cell lines, xenograft models, we observed increased DNMT1 , KMT2A expression in response to decitabine‐induced demethylation. Strikingly, protein was diminished all lines experienced degradation. Moreover, only cells with reduced levels showed biological effects following treatment. wild‐type, rearranged were locked G2 G1 cycle phases, respectively, likely due p27/p16 activation. Primary sample gene profiling confirmed different patterns between translocated cells. This newly discovered mode action via degradation evokes anti‐leukemic activity adult ALL cells, can act synergistically menin inhibition. Following successful clinical implementation for myeloid leukemia, drug should be considered potential promising addition therapeutic portfolio as well.

Language: Английский

Citations

0
Integrative genome-wide aberrant DNA methylation and transcriptome analysis identifies diagnostic markers for colorectal cancer DOI

Hengyang Shen,

Zhenling Wang, Yang Chen

et al.

Archives of Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Language: Английский

Citations

0
The ZBTB24-CDCA7-HELLS axis suppresses the totipotent 2C-like reprogramming by maintaining Dux methylation and repression DOI Creative Commons

Dan Guo,

Zeling Du,

Youqi Liu

et al.

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(7)

Published: April 10, 2025

Abstract Two-cell-like cells (2CLCs), a rare population (∼0.5%) in mouse embryonic stem cell (mESC) cultures, are transient totipotent-like state resembling that of 2C-stage embryos, and their discovery characterization have greatly facilitated the study early developmental events, such as zygotic genome activation. However, molecular determinants governing 2C-like reprogramming remain to be elucidated. Here, we show ZBTB24, CDCA7, HELLS, components pathway is involved pathogenesis immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, function negative regulators by maintaining DNA methylation Dux cluster, master inducer state. Disruption ZBTB24-CDCA7-HELLS axis results hypomethylation derepression, leading dramatic upregulation 2C-specific genes, which can reversed site-specific re-methylation promoter. We also provide evidence CDCA7 enriched at cluster recruits CDCA7–HELLS chromatin remodeling complex constitutive heterochromatin. Our uncovers key role for safeguarding mESC suppressing reprogramming.

Language: Английский

Citations

0
Induction of DNA Demethylation: Strategies and Consequences DOI Creative Commons
Pietro Salvatore Carollo, Viviana Barra

Epigenomes, Journal Year: 2025, Volume and Issue: 9(2), P. 11 - 11

Published: April 12, 2025

DNA methylation is an important epigenetic modification with a plethora of effects on cells, ranging from the regulation gene transcription to shaping chromatin structure. Notably, occurs thanks activity methyltransferases (DNMTs), which covalently add methyl group cytosine in position 5′ CpG dinucleotides. Different strategies have been developed study involving either DNMTs inhibition (passive demethylation) or use Ten-eleven translocation protein (TET) family enzymes, directly demethylate (active demethylation). In this manuscript, we will briefly cover most commonly used last two decades achieve demethylation, along their cells. We also discuss some newest inducible ways inhibit without remarkable side effects, as well effect non-coding RNAs methylation. Lastly, examine biomedical research.

Language: Английский

Citations

0