419A Life Science Center II
The acquisition and maintenance of cell fate identities is essential for normal development and tissue physiology. However, the molecular mechanisms safeguarding cell fate identity remain largely unclear. Our interest is to determine the epigenetic and transcriptional programs underlying cell fate changes towards stem cell-like states involved in cancer initiation. We use somatic cellular reprogramming into induced pluripotent stem cells (iPSCs), epithelial-to-mesenchymal (EMTs) cellular transitions and cancer stem cells (CSCs), as model systems. Our main projects are:
1) DNA oxidations in cancer stem cells.
TET enzymes are DNA dioxygenases that can sequentially convert methylated DNA (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). These DNA oxidations are intermediates during DNA demethylation and can also serve as epigenetic elements regulating gene expression. TET enzymes are required for cellular reprogramming into iPSCs as well as epithelial-to-mesenchymal cellular transitions. Aberrant TET-mediated DNA oxidations are found in various types of cancers. However, the transcriptional mechanisms dependent on DNA oxidations influencing stem cell-driven cancer initiating processes, remain undetermined. We are investigating the role of DNA oxidations in cancer stem cell-based model systems.
2) Transcriptional mechanisms triggering cancer initiation.
RNA Polymerase II (Pol II) promoter-proximal pausing is a prominent regulatory step during transcription elongation, and it is implicated in various aspects of cellular physiology including cell fate changes during embryonic development, epithelial-to-mesenchymal transitions and carcinogenesis. Pol II pausing can alter gene expression patterns leading to the amplification of oncogenes and/or repression of tumor suppressors. We are investigating how Pol II pausing impact cell fate transitions leading to the formation of cancer-stem cells.
3) Circadian rhythms versus cellular reprogramming.
Circadian rhythms are required for cellular and tissue homeostasis. Deficient circadian rhythms are implicated in various diseases including cancer. Notably, cellular reprogramming into iPSCs triggers the loss of circadian rhythms. However, the mechanisms involved in the disappearance of circadian rhythms during cellular reprogramming are unknown. We are investigating the epigenetic and transcriptional regulatory mechanisms underlying the loss of circadian rhythms and its impact in cellular reprogramming towards cancer stem cell-like states.
DNA oxidations as epigenetic elements regulating cell fate identity. Transcriptional mechanisms triggering cancer initiation. Circadian rhythms and cancer-stem cells.
Etchegaray J-P, et al., (2019). The histone deacetylase SIRT6 controls transcription elongation via promoter-proximal pausing. Molecular Cell (under revision).
Etchegaray J-P and Mostoslavsky R (2018). A sirtuin’s role in preventing senescence by protecting ribosomal DNA. J Biol Chem 293: 11251-11252.
Etchegaray J-P, et al., (2016). Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Molecular Cell 62: 695-711.
Etchegaray J-P and Mostoslavsky R (2015). Cell fate by SIRT6 and TETs. Cell Cycle 14: 1-2.
Etchegaray J-P, et al., (2015). The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosnie. Nature Cell Biology 17: 545-557.
Etchegaray J-P and Mostoslavsky R (2011). Energizing pluripotent gene transcription. Cell Stem Cell 9(4): 285-286.
Etchegaray J-P, et al., (2010). Casein kinase 1 delta (CK1d) regulates period length in the mouse suprachiasmatic circadian clock in vitro. PLoS One 5(4): e10303.
Etchegaray J-P, et al., (2009). Casein kinase 1 delta regulates the pace of the mammalian circadian clock. Molecular and Cellular Biology 29: 3853-3866.
Etchegaray J-P, et al., (2006). The polycomb group protein EZH2 is required for mammalian circadian clock function. Journal of Biological Chemistry 281: 21209-21215.
Etchegaray J-P, et al., (2003). Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421: 177-182.
Lee C, Etchegaray J-P, et al., (2001). Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107: 855-867.