TY - JOUR AB - Methylation of CG dinucleotides (mCGs), which regulates eukaryotic genome functions, is epigenetically propagated by Dnmt1/MET1 methyltransferases. How mCG is established and transmitted across generations despite imperfect enzyme fidelity is unclear. Whether mCG variation in natural populations is governed by genetic or epigenetic inheritance also remains mysterious. Here, we show that MET1 de novo activity, which is enhanced by existing proximate methylation, seeds and stabilizes mCG in Arabidopsis thaliana genes. MET1 activity is restricted by active demethylation and suppressed by histone variant H2A.Z, producing localized mCG patterns. Based on these observations, we develop a stochastic mathematical model that precisely recapitulates mCG inheritance dynamics and predicts intragenic mCG patterns and their population-scale variation given only CG site spacing. Our results demonstrate that intragenic mCG establishment, inheritance, and variance constitute a unified epigenetic process, revealing that intragenic mCG undergoes large, millennia-long epigenetic fluctuations and can therefore mediate evolution on this timescale. AU - Briffa, Amy AU - Hollwey, Elizabeth AU - Shahzad, Zaigham AU - Moore, Jonathan D. AU - Lyons, David B. AU - Howard, Martin AU - Zilberman, Daniel ID - 14551 IS - 11 JF - Cell Systems SN - 2405-4712 TI - Millennia-long epigenetic fluctuations generate intragenic DNA methylation variance in Arabidopsis populations VL - 14 ER - TY - JOUR AB - Mutations are acquired frequently, such that each cell's genome inscribes its history of cell divisions. Common genomic alterations involve loss of heterozygosity (LOH). LOH accumulates throughout the genome, offering large encoding capacity for inferring cell lineage. Using only single-cell RNA sequencing (scRNA-seq) of mouse brain cells, we found that LOH events spanning multiple genes are revealed as tracts of monoallelically expressed, constitutionally heterozygous single-nucleotide variants (SNVs). We simultaneously inferred cell lineage and marked developmental time points based on X chromosome inactivation and the total number of LOH events while identifying cell types from gene expression patterns. Our results are consistent with progenitor cells giving rise to multiple cortical cell types through stereotyped expansion and distinct waves of neurogenesis. This type of retrospective analysis could be incorporated into scRNA-seq pipelines and, compared with experimental approaches for determining lineage in model organisms, is applicable where genetic engineering is prohibited, such as humans. AU - Anderson, Donovan J. AU - Pauler, Florian AU - Mckenna, Aaron AU - Shendure, Jay AU - Hippenmeyer, Simon AU - Horwitz, Marshall S. ID - 11449 IS - 6 JF - Cell Systems SN - 2405-4712 TI - Simultaneous brain cell type and lineage determined by scRNA-seq reveals stereotyped cortical development VL - 13 ER -