Epigenetic memory in disease

We are currently developing three research lines in the lab:

What is the molecular foundation of epigenetic memory?

To treat epigenetic-based diseases we first need to establish the key molecular epigenetic pathways that facilitate the formation and functioning of complex multicellular organisms like humans. Upon fusion of the sperm and oocyte cells, a single cell named the zygote is formed. The zygote has a unique genome and during organism development it goes through a vast number of proliferation and differentiation rounds that generate over 10¹² cells that are genetically identical but functionally distinct, and that self-organise to produce 78 organs that compose the adult human body. Cell specialization depends on the establishment of distinct epigenetic configurations that facilitate the expression of set of cell-type-specific genes. Thus, cell-type-specific epigenetic patterns need to be “memorized” and maintained for a lifetime, because the original differentiation signal instructing the change in gene expression during prenatal life is no longer present during the adult life. Importantly, different types of environmental stimulus can perturb the cells’ epigenetic memory, and thus we hypothesize that many diseases associated to aging are a consequence of the perturbation of the original epigenetic configuration that was laid on the genome during development. In our lab we are dissecting the mechanism by which epigenetic regulators promote the mantainance of epigenetic memory. In particular, we study the molecular details as to how two hallmark epigenetic systems (Polycomb proteins and H3K9 methyltransferases) enable the perpetuation of transcriptional memory in mouse pluripotent stem cells. Our recent findings ^1,2 suggest that cellular memory is supported by an epigenetic cycle in which reversible activities carried out by epigenetic regulators in coordination with cell cycle transition create a multiphasic system that can accommodate both maintenance of cell identity and cell differentiation in proliferating stem cell populations ³.

Is the loss of epigenetic information the reason we age? Can we slow down the pace of aging using drugs that stabilize our epigenome?

Deciphering the molecular basis of human aging is an exciting challenge in fundamental biology with great implications in public health. Emerging reports suggest that aging can be induced by environmental factors that challenge the stability of epigenetic information stored on our genomes. We support the idea that the aging process is driven by the progressive loss of “youthful epigenetic information” laid during development, the retrieval of which via epigenetic reprogramming can improve the function of damaged and aged tissues by catalysing age reversal ⁴. Using pluripotent cells and mutant mice as model systems, we are currently investigating which are the epigenetic factors that constitute our young epigenome, and that protects us from aging during lifespan. We envision that characterization of such mechanisms will provide a better understanding of the molecular basis of epigenetic memory and allow us to devise safe pharmacological interventions that protect us from the loss of youth-encoding epigenetic memory during our lifespan.

Is epigenetic instability a driver of cancer progression? Can we cure cancer by modulating the cancer epigenome?

Cancer is one of the most prevalent diseases in aged populations. Metastasis is the cause of ~90% of cancer-associated mortality and therefore, to cure cancer, it is urgent to develop new therapies that block the capacity of cancer cells to disseminate throughout the human body. Metastatic dissemination relies on the continuous positive selection of cancer cells that are functionally optimized to survive in the different physiological and pharmacological environments occurring during disease progression. In our lab, we believe that the functional cell-to-cell heterogeneity that drives cancer progression relies, not only on different combination of genetic mutations accumulated in their genome, but also on distinct epigenetic configurations that dictate the behaviour of individual cells ⁵. We use cancer cells derived from human patients and mouse xenotransplant models to investigate how epigenetic memory affects cancer progression, with the aim to contribute to the development of new therapies that block disease progression by targeting epigenetic regulators. We have recently demonstrated that the epigenetic proteins Polycomb enable phenotypic epithelial-mesenchymal plasticity in cancer cells that facilitate metastatic dissemination ^6,7. These findings provide key information for effective application of currently available Polycomb inhibitors in human cancer patients.

Bibliography

1. Asenjo, H. G. et al. Changes in PRC1 activity during interphase modulate lineage transition in pluripotent cells. Nat Commun 14, 180, doi:10.1038/s41467-023-35859-9 (2023).
2. Asenjo, H. G. et al. Polycomb regulation is coupled to cell cycle transition in pluripotent stem cells. Science advances 6, eaay4768, doi:10.1126/sciadv.aay4768 (2020).
3. Espinosa-Martínez, M., Alcázar-Fabra, M. & Landeira, D. The molecular basis of cell memory in mammals: The epigenetic cycle. Science advances 10, eadl3188, doi:10.1126/sciadv.adl3188 (2024).
4. Lu, Y. R., Tian, X. & Sinclair, D. A. The Information Theory of Aging. Nature aging 3, 1486-1499, doi:10.1038/s43587-023-00527-6 (2023).
5. Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, doi:10.1126/science.aal2380 (2017).
6. Gallardo, A. et al. EZH2 represses mesenchymal genes and upholds the epithelial state of breast carcinoma cells. bioRxiv, 2023.2003.2013.532335, doi:10.1101/2023.03.13.532335 (2023).
7. Gallardo, A. et al. EZH2 endorses cell plasticity to non-small cell lung cancer cells facilitating mesenchymal to epithelial transition and tumour colonization. Oncogene 41, 3611-3624, doi:10.1038/s41388-022-02375-x (2022).

• • Universidad de Granada.
  • Consejería de salud de la Junta de Andalucía.
  • Consejería de economía, conocimiento, empresas y universidad de la Junta de Andalucía.
  • Asociación española contra el cáncer.
  • Instituto de Salud Carlos III.
  • Ministerio de educación, ciencia y universidades.
  • Laboratorio miembro de la red “Regulatory Genomics Network” (Red Temática AEI) y “EpiGene3Sys” (CNRS/European Comission).

• • Omics analysis of DNA, RNA and proteins using state of the art equipment.
  • Single-cell analysis of DNA, RNA and proteins using state of the art platforms.