419A Life Sciences Center
The acquisition and maintenance of cell fate identities is essential for normal development and adult 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 occurring during embryonic development, malignant transformations and aging restoration. Our main projects involve:
1) DNA oxidations:
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. We are investigating how TET-mediated DNA oxidations functioning as epigenetic elements regulate cancer dormancy and the restoration of aging.
2) Transcriptional pausing/elongation:
RNA Polymerase II (Pol II) promoter-proximal pausing is a regulatory step during transcription elongation. We are studying the crosstalk between epigenetic dynamics and transcriptional pausing in the context of aging restoration, early embryonic development and cancer dormancy.
3) Circadian rhythms:
Circadian rhythms are required for cellular and tissue homeostasis. Deficient circadian rhythms are implicated in various diseases. We are investigating how the epigenome modulates circadian rhythms and its impact in cell fate changes.
Topics in Biology
2019 Initiative for Multidisciplinary Research Team (IMRT) Award
2020 Busch Biomedical Foundation Award
Cell fate changes
Greco SJ, Ayer S, Guiro K, Sinha G, Donnelly RJ, El-Far M, Pamarthi SH, Sandiford OA, Gergues M, Sherman LS, Schonning MJ, Etchegaray JP, Ponzio NM, Ramaswamy N, and Rameshwar P. (2020). Exosome-mediated hematopoietic rejuvenation in a humanized mouse model indicate potential for cancer immunotherapy. bioRxiv
Sandiford O, Donnelly R, El-Far M, Burmeyer L, Sinha G, Pamarthi SH, Sherman L, Ferrer A, DeVore A, Patel S, Naaldijk Y, Alonso S, Barak P, Bryan M, Ponzio N, Narrayanan R, Etchegaray JP, Kumar R, and Rameshwar P. Mesenchymal stem cell secreted extracellular vesicle instructs stepwise dedifferentiation of breast cancer cells into dormancy at bone marrow perivascular region. Cancer Research (In press).
Kumar S, Gonzalez EA, Rameshwar P, Etchegaray JP. (2020). Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies. Cancers 12: 3657
Ferrer A, Roser CT, El-Far MH, Savanur VH, Eljarrah A, Gergues M, Kra JA, Etchegaray JP, Rameshwar P. (2020). Hypoxia-mediated changes in bone marrow microenvironment in breast cancer dormancy. Cancer Lett 488: 9-17.
Ferrer A, Trinidad JR, Sandiford O, Etchegaray JP, Rameshwar P. (2020). Epigenetic dynamics in cancer stem cell dormancy. Cancer Metastasis Rev 39: 721-738.
Etchegaray JP, et al., (2019). The histone deacetylase SIRT6 controls transcription elongation via promoter-proximal pausing. Molecular Cell 75: 683-699.
Etchegaray JP and Mostoslavsky R (2018). A sirtuin’s role in preventing senescence by protecting ribosomal DNA. J Biol Chem 293: 11251-11252.
Etchegaray JP, et al., (2016). Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Molecular Cell 62: 695-711.
Etchegaray JP and Mostoslavsky R (2015). Cell fate by SIRT6 and TETs. Cell Cycle 14: 1-2.
Etchegaray JP, 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 JP and Mostoslavsky R (2011). Energizing pluripotent gene transcription. Cell Stem Cell 9(4): 285-286.
Etchegaray JP, 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 JP, et al., (2009). Casein kinase 1 delta regulates the pace of the mammalian circadian clock. Mol Cell Biol 29: 3853-3866.
Etchegaray JP, et al., (2006). The polycomb group protein EZH2 is required for mammalian circadian clock function. J Biol Chem 281: 21209-21215.
Etchegaray JP, et al., (2003). Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421: 177-182.
Lee C, Etchegaray JP, et al., (2001). Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107: 855-867.