Dr. Miguel Ramalho-Santos

• 2019–present; Professor, Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto
• 2018–present; Senior Investigator, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto

Former appointments

• 2018–2019; Associate Professor, Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto
• 2013–2018; Associate Professor, Obstetrics and Gynecology and Pathology, Centers for Regeneration Medicine and Reproductive Sciences, Diabetes Center, Og/Gyn and Pathology, School of Medicine, University of California, San Francisco, CA, USA
• 2006–2018; Co-Director, Lentiviral Core Facility, Diabetes and Endocrinology Research Center Diabetes Center, School of Medicine, University of California, San Francisco, CA, USA
• 2007–2013; Assistant Professor, Obstetrics and Gynecology and Pathology, Centers for Regeneration Medicine and Reproductive Sciences, Diabetes Center, Ob/Gyn and Pathology, School of Medicine, University of California, San Francisco, CA, USA

• UCSF Fellow, Developmental and Stem Cell Biology Program, Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, CA, USA; 2003–2007
• Post-doctorate in Developmental Biology, Harvard University, Cambridge, MA, USA; 2002–2003
• PhD in Biochemistry, Harvard University, Cambridge, Massachusetts, MA, USA; 1997–2002
• MSc in Cellular and Molecular Biology, University of Coimbra, Coimbra, Portugal; 1995–1997
• BSc in Biology (Zoology), University of Coimbra, Coimbra, Portugal; 1990–1995

• 2025 – Anne and Max Tanenbaum Chair in Molecular Medicine Mount Sinai Hospital
• 2017 – Canada 150 Research Chair in Developmental Epigenetics Government of Canada
• 2016 – Royan International Research Award in Reproductive Genetics Royan Institute, Tehran, Iran
• 2008 – NIH Director's New Innovator Award NIH Director's Office, USA
• 2004 – Champion for Diversity University of California, San Francisco
• 1997 – Fellowship for PhD Abroad, Ministry for Science and Technology, Portugal

Stem cell hypertranscription

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. 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 (Kim Cell Reports 2023) 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 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 hypertranscription (Gaspar-Maia Nature 2009, Guzman-Ayala Development 2015, Bulut-Karslioglu Nature Communications 2021). Hypertranscription has recently been shown to be pervasive in aggressive cancers, highlighting its relevance in disease contexts. We are continuing to explore the molecular mechanisms and developmental roles of hypertranscription. 

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Developmental pausing

We found that the permissive chromatin state and hypertranscription of pluripotent stem cells are acutely tuned to their translational capacity, itself dependent on nutrient availability (Bulut-Karslioglu Cell Stem Cell 2018). This work led to the discovery of a paused pluripotent state in mouse embryonic stem cells and blastocysts, induced by mTor inhibition (Bulut-Karslioglu Nature 2016).  This state of “suspended animation” models one that occurs in wild animals, called diapause, whereby blastocysts reversibly arrest development during periods of unfavorable environmental conditions. The ability to reversibly suspend the development of a mammal in the laboratory, and to mimic such developmental pausing in embryonic stem cells, offers a tractable model to dissect a number of fascinating questions. We have discovered that RNA methylation is critical to maintain the paused state and identified the underlying mechanisms (Collignon Nature Cell Biology 2023). 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 interested in understanding the regulation of developmental pausing and are exploring other models of embryonic dormancy.

Transposons in development

Unique protein-coding genes occupy only a minor fraction (~1.5 per cent) 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 ES 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 partners with the protein Nucleolin to regulate the expression of ribosomal RNA and the 2-cell program. Via this mechanism, LINE1/Nucleolin are required for early development and for self-renewal of ES 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. We continue to explore novel roles for TE and repeat elements in transcription and development.

Environment-epigenome-development

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 diseases linked to deficiencies in the activity of Tets, including several types of cancer. 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. 

We are always looking for motivated researchers to join our team.

Postdocs 
Our research group is always interested in recruiting highly motivated and creative postdoctoral fellows from diverse fields. Please forward your CV, the contact of 3 references and a cover letter explaining why you are interested in our lab to [email protected].

Graduate students
Our research group is part of the Department of Molecular Genetics, at the Temerty Faculty of Medicine at University of Toronto. The Molecular Genetics Graduate Program involves 3 rotations in 3 different labs during the first semester, so students do not need to be pre-accepted to a particular lab. Graduate students interested in doing a PhD in our laboratory are encouraged to apply directly to the program. They can also contact [email protected] if interested.

Undergraduate students
There are various opportunities for undergraduate students to work in our lab, both doing the school year and the summer. We take U of T undergraduate students from the Molecular Genetics or Human Biology programs. Other students can also apply for summer opportunities to the Research Training Center (RTC) at the Lunenfeld-Tanenbaum Research Institute. Applications are available online and need to be filled by February 28th of each year.