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

Zhou, Wanding; Hinoue, Toshinori; Barnes, Bret; Mitchell, Owen; Iqbal, Waleed; Lee, Sol Moe; Foy, Kelly K.; Lee, Kwang-Ho; Moyer, Ethan Jacob; VanderArk, Alexandra; Koeman, Julie; Ding, Wubin; Kalkat, Manpreet; Spix, Nathan J; Eagleson, Bryn; Pospisilik, J. Andrew; Szabó, Piroska E.; Bartolomei, Marisa S.; Schaaf, Nicole A. Vander; Kang, Liang; Wiseman, Ashley K.; Jones, Peter A.; Krawczyk, Connie M.; Adams, Marie; Porecha, Rishi; Chen, Brian H.; Shen, Hui; Laird, Peter W.

doi:10.1101/2022.03.24.485667

Cited by 9 publications

(6 citation statements)

References 185 publications

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“…S3E ). This is consistent with TRIM28’s known role in gene silencing 37,38,40,41,56 . Interestingly, Tp53 R270H/+ animals also showed early-life epigenetic changes, and these showed some similarity to Trim28 +/D9 -induced changes ( Fig.…”

Section: Resultssupporting

confidence: 87%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility ′states′ in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

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Section: Resultssupporting

confidence: 87%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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“…The Illumina Infinium Mouse Methylation-12v1-0 BeadChip includes 284760 CG probes, 1,352 high-frequency SNP probes (rs probes), and 938 non-CpG targeting probes (Ch probes) (287,050 probes total) as defined in “Infinium Mouse Methylation v1.0 A1 GS Manifest File. bpm” ( Zhou et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Placental Abnormalities are Associated With Specific Windows of Embryo Culture in a Mouse Model

Vrooman

Rhon‐Calderón

Suri

et al. 2022

Front. Cell Dev. Biol.

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Assisted Reproductive Technologies (ART) employ gamete/embryo handling and culture in vitro to produce offspring. ART pregnancies have an increased risk of low birth weight, abnormal placentation, pregnancy complications, and imprinting disorders. Embryo culture induces low birth weight, abnormal placental morphology, and lower levels of DNA methylation in placentas in a mouse model of ART. Whether preimplantation embryos at specific stages of development are more susceptible to these perturbations remains unresolved. Accordingly, we performed embryo culture for several discrete periods of preimplantation development and following embryo transfer, assessed fetal and placental outcomes at term. We observed a reduction in fetal:placental ratio associated with two distinct windows of preimplantation embryo development, one prior to the morula stage and the other from the morula to blastocyst stage, whereas placental morphological abnormalities and reduced imprinting control region methylation were only associated with culture prior to the morula stage. Extended culture to the blastocyst stage also induces additional placental DNA methylation changes compared to embryos transferred at the morula stage, and female concepti exhibited a higher loss of DNA methylation than males. By identifying specific developmental windows of susceptibility, this study provides a framework to optimize further culture conditions to minimize risks associated with ART pregnancies.

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“…4k). In contrast, the recently described BeadChip multi-tissue epigenetic clock 35 —the only mouse microarray-based clock that is commercially available—uniformly underpredicted the age of samples, possibly owing to a skewed age and sample distribution in the original study 35 . Finally, the RRBS-based mouse blood clock 11 predicted samples with more accuracy than the BeadChip clock but with more variation than TIME-Seq.…”

Section: Resultsmentioning

confidence: 92%

“…For clock analysis, the TIME-Seq mouse blood and multi-tissue clocks were applied to TIME-Seq data as described above, whereas the RRBS-based mouse blood clock was applied in a similar fashion using the reported loci, weights, and formula 12 , replacing any missing values with the mean methylation from all other samples. The BeadChip clock was applied to BeadChip data as reported 56 .…”

Section: Methodsmentioning

confidence: 99%

TIME-Seq Enables Scalable and Inexpensive Epigenetic Age Predictions

Griffin¹,

Kane²,

Trapp

et al. 2021

Preprint

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Epigenetic “clocks” based on DNA methylation (DNAme) are the most robust and widely employed aging biomarker. They have been built for numerous species and reflect gold-standard interventions that extend lifespan. However, conventional methods for measuring epigenetic clocks are expensive and low-throughput. Here, we describe Tagmentation-based Indexing for Methylation Sequencing (TIME-Seq) for ultra-cheap and scalable targeted methylation sequencing of epigenetic clocks and other DNAme biomarkers. Using TIME-Seq, we built and validated inexpensive epigenetic clocks based on genomic and ribosomal DNAme in hundreds of mice and human samples. We also discover it is possible to accurately predict age from extremely low-cost shallow sequencing (e.g., 10,000 reads) of TIME-Seq libraries using scAge, a probabilistic age-prediction algorithm originally applied to single cells. Together, these methods reduce the cost of DNAme biomarker analysis by more than two orders of magnitude, thereby expanding and democratizing their use in aging research, clinical trials, and disease diagnosis.

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

Cited by 9 publications

References 185 publications

Developmental priming of cancer susceptibility

Developmental priming of cancer susceptibility

Placental Abnormalities are Associated With Specific Windows of Embryo Culture in a Mouse Model

TIME-Seq Enables Scalable and Inexpensive Epigenetic Age Predictions

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