Biology subjects

Cedar, H.

Publications and source records attributed to Cedar, H..

3 recordsLinked to original sources

bioRxiv2026

Cell-to-cell variability and gain of methylation at polycomb CpG islands as a hallmark of aging

Aging is a complex multifactorial process that affects cellular function and tissue homeostasis over time. Despite extensive research, the molecular mechanisms driving cellular aging remain poorly understood1,2. Many studies have focused on changes in DNA methylation as an indicator of aging3. In particular, the degree of methylation at polycomb CpG islands has been shown to be predictive of phenotypic changes associated with aging4,5. Since many age-related pathological processes, are thought to be of single-cell origin (e.g. cancer), we questioned whether polycomb DNA methylation also occurs preferentially in a subset of cells within the overall population. Using single-cell whole-genome methylation data from multiple ages and tissues, we identify Average Polycomb CpG Methylation as a hallmark of cellular aging. This revealed that aging occurs at varying rates within specific cells, with faster proliferating cells showing accelerated levels. Gene expression analysis in "young" and "old" single cells identified changes in immune response, translation regulation, tumorigenesis, neurodegeneration and other cellular processes associated with aging. These results challenge traditional models of homogeneous cellular aging and suggest that aging itself is a highly individualized process at the single-cell level that may be driven by programmed changes in polycomb CpG island DNA methylation.

genomics↗

bioRxiv2025

The genetic basis for DNA methylation variation across tissues and development

The mechanisms by which genetic variation shapes the epigenome across cell types and developmental stages have remained elusive. Here, we define a unifying developmental framework for DNA methylation programming, grounded in genome-wide methylation and genetic variation data from both mouse and human. In mice, we identify thousands of differentially methylated regions (DMRs) linked to sequence polymorphisms that disrupt transcription factor binding. These DMRs are programmed either during implantation or later in organogenesis, revealing two distinct periods of epigenetic regulation. Extending this logic to humans, we analyze our atlas of over 200 WGBS samples from 39 purified cell types and map 33,574 regions where common SNPs control allele-specific methylation. These include both early-established and cell-type-specific loci, many of which colocalize with eQTLs, enhancers, silencers, and disease-associated variants. Our results uncover a widespread mechanism by which genetic variation influences the regulatory landscape, linking sequence, methylation, and transcription across tissues. This cross-species atlas of sequence-dependent methylation not only clarifies the logic and timing of epigenetic programming, but also provides a foundational resource for deciphering non-coding variants in development, complex disease, and regenerative medicine.

genomics↗

bioRxiv2021

Pluripotency-Independent Induction of Human Trophoblast Stem Cells from Fibroblasts

Recent studies demonstrated that human trophoblast stem-like cells (hTS-like cells) can be derived from naive embryonic stem cells or be induced from somatic cells by the pluripotency factors, OSKM. This raises two main questions; (i) whether human induced TSCs (hiTSCs) can be generated independently to pluripotent state or factors and (ii) what are the mechanisms by which hTSC state is established during reprogramming. Here, we identify GATA3, OCT4, KLF4 and MYC (GOKM) as a pluripotency-independent combination of factors that can generate stable and functional hiTSCs, from both male and female fibroblasts. By using single and double knockout (KO) fibroblasts for major pluripotency genes (i.e. SOX2 or NANOG/PRDM14) we show that GOKM not only is capable of generating hiTSCs from the KO cells, but rather that the efficiency of the process is increased. Through H3K4me2 and chromatin accessibility profiling we demonstrate that GOKM target different loci and genes than OSKM, and that a significant fraction of them is related to placenta and trophoblast function. Moreover, we show that GOKM exert a greater pioneer activity compared to OSKM. While GOKM target many specific hTSC loci, OSKM mainly target hTSC loci that are shared with hESCs. Finally, we reveal a gene signature of trophoblast-related genes, consisting of 172 genes which are highly expressed in blastocyst-derived TSCs and GOKM-hiTSCs but absent or mildly expressed in OSKM-hiTSCs. Taken together, these results imply that not only is the pluripotent state, and SOX2 specifically, not required to produce functional hiTSCs, but that pluripotency-specific factors actually interfere with the acquisition of the hTSC state during reprogramming.

cell biology↗