Modeling disease through cell reprogramming

We harness the unprecedented potential of cell reprogramming to develop physiopathologically meaningful models of both neurodevelopmental disorders and cancer.

One of the most tangible outputs of somatic cell reprogramming has been a paradigm shift in our ability to model human diseases, for which fundamental limitations have been so far: i) the scarce availability of primary diseased tissues, which is particularly salient for disorders of the nervous system; and ii) the difficulty of reconstructing disease history, which is salient also for cancer pathogenesis.
We are thus harnessing the unprecedented potential of cell reprogramming to develop physiopathologically meaningful models of both neurodevelopmental disorders and cancer, thereby aiming at the dissection of the genomic versus epigenomic components of their pathogenesis.
Specifically, within neurodevelopmental disorders we focus on a unique range of intellectual disability syndromes (including autism spectrum disorders) caused by mutations or dosage alterations in epigenetic regulators and transcription factors.
As far as cancer is concerned, we focus on ovarian cancer, a critical example of unmet medical need due to the lack of relevant cellular models and the very limited understanding of the developmental aberrations that underlie its pathogenesis.

Browse our projects in more detail:

  • Neurodevelopmental disorders
    • Williams-Beuren Syndrome and 7q11.23 microduplication Syndrome
    • Kabuki Syndrome
    • ADNP-related autistic spectrum disorders
    • Weaver Syndrome
    • YY1-associated intellectual disability
  • Ovarian cancer
    • Dissection of epigenetic and genetic contributions to ovarian cancer pathogenesis
    • Identification of the cell of origin in ovarian cancer

Epigenetic regulation of neural fate

We study the role of two major pathways of chromatin regulation, methylation of histone H3 on lysine tails 4 and 27, on the acquisition of neuronal fate, with a special focus on corticogenesis.

The methylations of histone H3 on lysine tails 4 and 27 (H3K4me and H3K27me), respectively mediated by the Trithorax (Trx) and Polycomb (PcG) protein families, are central regulators of the establishment and maintenance of differentiated cell states. In particular, the central nervous system has become a paradigm-setting model to define the functional relevance of H3K27me for cell fate transitions, with the realization that this mark is dynamically regulated throughout neuronal differentiation by the interplay of methyltransferases and demethylases.
Following the identification of JMJD3 as the first enzyme that antagonizes Polycomb silencing by demethylating H3K27 (De Santa et al. Cell 2007), our key contributions include the characterization of its essential role for the early neural commitment of embryonic stem cells (Burgold et al. PLoS One, 2008), and the discovery that aberrations in H3K27 methylation caused by JMJD3 loss in neural precursors impact the late maturation and function of neuronal circuits (Burgold et al. Cell Reports 2012). We are now using conditional approaches to study the role that H3K27me and H3K4me play in the expansion of neural stem cells and the sequential acquisition of neuronal fate during murine corticogenesis (Testa Bioessays 2011).

Browse our projects in more detail:

  • Epigenetic regulation of corticogenesis in mice models

Aberrant genome programming in brain cancer

Consistent with the role of Polycomb-mediated H3K27 methylation in lineage choices, this line of research investigates the oncogenic counterpart of the acquisition of neural fate, focusing on malignant gliomas, combining advanced murine models with the analysis of human tumors.

Alterations in H3K27me figure prominently among the epigenetic aberrations of cancer. Furthermore, the majority of genes that are CpG hypermethylated in cancer are pre-marked by H3K27me3 in embryonic stem cells, suggesting that the Polycomb-dependent gene expression program that orchestrates development in normal cells is hijacked in cancer cells as the main template for cancer DNA methylation.
Hence, this line of research in the lab investigates the oncogenic counterpart of the acquisition of neural fate, focusing on malignant gliomas with the aim of elucidating the epigenetic basis of the lineage aberrations that characterize this disease. Specifically, we test the proposition that loss of the physiologic regulation centered around H3K27me3 is important for the initiation and/or maintenance of gliomas, combining the conditional modulation of this epigenetic axis in advanced murine models of glioblastoma with its functional dissection in primary cells isolated from both primary and recurrent human high grade gliomas.

Browse our projects in more detail:

  • Role of Polycomb Repressive Complex proteins in glioblastoma multiforme
  • Epigenetic basis of glioblastoma recurrence in humans

Epigenetics of cell fate reprogramming

Finally, consistent with the role of the Trithorax and Polycomb families in cell fate transitions, we study their contribution to cell fate reassignment, both for induced pluripotency and direct transdifferentiation.

Widespread changes in H3K4 and H3K27 methylation have been shown to accompany transcription factor-induced cell fate reassignment. Our objective is to dissect functionally their relative contribution to cell fate reassignment, using both experimental paradigms of induced pluripotency – where fibroblasts are reprogrammed to induced pluripotent stem cells (iPSC) – and direct transdifferentiation, where fibroblasts are reprogrammed to induced neuronal cells (iNCs). Our recent contribution includes the discovery that in iPSC generation, Polycomb-mediated H3K27 trimethylation is required on a highly selective core of Polycomb targets, setting stage for defining the functional relevance of this core gene subset in other physiopathological paradigms of cell reprogramming, including cancer (Fragola et al. PLoS Genetics 2013).

Browse our projects in more detail:

  • Role of Trithorax in transdifferentiation
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