Mammalian Developmental Epigenetics
With each generation, the precise spatio-temporal unfolding of embryonic development requires a tight orchestration of dynamic changes in chromatin states and corresponding transcriptional programs. While development is often approached as simply hardwired in the genome, there is a growing appreciation that the environment provides key inputs into the bookmarking and activation of the genome during ontogeny, but such inputs remain very poorly understood at the mechanistic level. Our lab is interested in understanding the genome-environment interactions that shape mammalian development and reproduction. Of particular interest are pluripotent cells that exist in the mammalian embryo and give rise to all cell types of the body. Recent work from our lab highlights that such foundational aspects as genome organization, transcription and environmental input are regulated in unique and novel ways in pluripotent cells of the early embryo and the germline. Our research is organized around 4 principal avenues of inquiry, each of which has several points of synergy with the other avenues.
Stem cell hypertranscription
Simon McGrath, “Who Left The Tap On”
The part of the genome that is activated, that is, transcribed into RNA, in any given cell, is called the transcriptome. The general assumption is that the overall level of the transcriptome does not change much between different cell types, and only a relatively small set of “outlier” genes that change in activity between cell types (so-called tissue-specific genes) are of interest. However, we have found that this assumption is incorrect in many settings, notably during development, in stem cells, and in various cancers.
The origin of our studies on hypertranscription can be traced back to Miguel’s PhD work on stem cell transcriptomics (Ramalho-Santos Science 2002, Kim Stem Cell Reports 2025). Hypertranscription, the global amplification of the transcriptome, is pervasive in stem/progenitor cells but has remained largely undetected until recently due to technical and analytic limitations that we have helped overcome (read our reviews on this topic: Percharde Dev Cell 2017, Kim Trends in Genetics 2024). We found that hypertranscription is critical for the growth of pluripotent cells at the time of implantation and for the expansion of definitive hematopoietic stem cells (Percharde Cell Rep 2017, Guzman-Ayala Development 2015, Koh Proc Natl Acad Sci USA 2015). We found that the chromatin remodeler Chd1 is an essential regulator of open chromatin and hypertranscription in embryonic stem cells (Gaspar-Maia Nature 2009, Guzman-Ayala Development 2015) and that it acts to promote repair of DNA breaks that accumulate at the promoters of protein coding genes and rDNA (Bulut-Karslioglu Nature Communications 2021). We developed methods to detect hypertranscription in single-cell RNA-seq data, and found that hypertranscription is remarkably pervasive in stem/progenitor cells across all major adult organs (Kim Cell Reports 2023). Our results indicate that hypertranscription is a general and dynamic cellular program that is recurrently employed during development, organ maintenance and regeneration. Hypertranscription has recently been shown to be pervasive in aggressive cancers, highlighting its relevance in disease contexts. We found that human CHD1 is required for an open chromatin landscape, transcriptional output and tumor formation driven by the MYC oncogene in a model of breast cancer. (Cho, Oncogene 2026). We are continuing to explore the molecular mechanisms and developmental roles of hypertranscription.
Developmental dormancy
Salvador Dalí, “The Disintegration of the Persistence of Memory”
Cells and organisms from across all kingdoms of the tree of life can enter dormancy to survive challenging environmental conditions, and this is thought to have been central to the evolution of life on Earth. Dormancy can occur during embryonic development, in adult stem cells and in hibernating species. Despite its broad relevance, dormancy remains poorly understood. We have been studying dormancy in early mouse development. We discovered that dormancy can be induced in mouse embryonic stem cells and blastocysts, by inhibition of mTor, a kinase that is a central regulator of growth (Bulut-Karslioglu Nature 2016, Bulut-Karslioglu Cell Stem Cell 2018). The ability to reversibly suspend the development of a mammal in the laboratory, and to mimic such developmental dormancy in embryonic stem cells, offers a tractable model to dissect a number of fascinating questions. We showed that m6A RNA methylation mediated by METTL3 is critical to maintain the transcriptionally suppressed state of dormancy by destabilization of mRNAs of growth promoting factors (Collignon Nature Cell Biology 2023). In parallel, we found that TGFbeta signaling via NODAL and SMAD2 is essential for dormancy by transcriptionally regulating lipid metabolism (Furlan bioRxiv 2025). Working with collaborators in Toronto, we have found that cancer cells highjack the same molecular and cellular pathways of diapause to survive chemotherapy in a dormant state so that they can later regrow tumors (Rehman Cell 2021). The results point to new strategies to target these dormant cancer cells. We are exploring new regulators of the entry into and exit from developmental dormancy.
Transposons in development
Vera Molnár, “(Des)Ordes”
Unique protein-coding genes occupy only a minor fraction (~1.5%) of our genome. About half of the mouse and human genomes is comprised of Transposable Elements (TEs), which are sequences capable of moving to different locations in the genome. While TEs are generally assumed to be parasitic elements detrimental to genome integrity, they are a major source of novelty during evolution and can have beneficial roles during development (Percharde Bioessays 2020). Interestingly, the TEs of the LINE1 and ERV families are repressed in most somatic cells but are highly expressed in mouse and human pre-implantation embryos and embryonic stem cells.
We found that RNA from mouse LINE1 orchestrates the progression of totipotent cells at the 2-cell stage towards pluripotent cells of the blastocyst. LINE1 RNA does this by partnering with the protein Nucleolin to regulate the expression of ribosomal RNA and the transcriptional program of the 2-cell program. Via this mechanism, LINE1/Nucleolin are required for early development and for self-renewal of embryonic stem cells (Percharde Cell 2018). Despite independent evolution of transposons in different mammalian lineages, we found that LINE1 plays a remarkably conserved role in human embryonic stem cells. LINE1 RNA promotes maintenance of genomic architecture of the nucleolus (Ataei Genes and Development 2024) and prevents developmental reversion to the 8-cell state, the equivalent of the mouse 2-cell state (Zhang Developmental Cell 2024). These results cast a fundamentally novel light on our understanding of early embryogenesis and pluripotency, with TEs as key orchestrators. In agreement with this notion, we found that another type of repeat elements, the Alpha Satellite Repeat (ALR), is expressed in naïve human embryonic stem cells, maintains the perinucleolar compartment, which was previously thought to only exist in cancer cells, and regulates ribosomal RNA synthesis (Mittal Genes and Development 2026). We continue to explore novel roles for TE and repeat elements in higher-order chromatin organization, transcriptional output (see also Stem cell hypertranscription) and developmental transitions.
Environment-epigenome-development
Katsushika Hokusai, “The Great Wave off Kanagawa”, adapted by Evelyne Collignon
Developmental and stem cell biologists often assume that development is a process hardwired in the genome and insulated from environmental influence. However, a growing body of evidence shows that deficiencies in maternal diet or exposure to environmental toxins during gestation may affect developmental trajectories and program postnatal disease propensity in the progeny. The mechanisms that underlie the environmental modulation of developmental and stem cell biology remain largely unknown.
We discovered that the essential nutrient Vitamin C impacts the transcriptional and epigenetic state of ES cells in remarkable ways by acting as a specific co-factor for Tet enzymes and greatly enhancing DNA demethylation (Blaschke Nature 2013). Using mouse models, we went on to show that dietary Vitamin C alters the epigenetic state and function of the fetal germline in vivo, recapitulating the Tet1 mutation, disrupting meiosis, and leading to sub-fertility in adulthood (Ditroia Nature 2019). Our findings have implications in other stem cell systems where Tet enzymes are active, including the hematopoietic system and the brain. In addition, deficiencies in the activity of Tets have been causally linked to several types of cancer. Our work contributed to a renewed interest in Vitamin C in cancer therapies. We are dissecting the impact of a variety of environmental stressors during gestation on epigenetic states in fetal cells and physiological outcomes into adulthood and across generations. These ongoing projects paint a picture of the mammalian embryo being highly attuned to variations in environmental factors and capable of discriminating their nature at the molecular, developmental and physiological levels. These findings have implications for our understanding of intergenerational programming of disease, particularly in the broader context of rising environmental contamination and the ongoing climate crisis.