Alternative fate repression in neuronal specification – ALT-F-R

The proper functioning of the human nervous system relies on the generation of a diverse and precisely organized set of neuronal types. Disruptions in this cellular composition has been associated to various neurodevelopmental disorders (NDDs), including autism spectrum disorders. Neuronal diversity emerges during development through the combinatorial activity of transcription factors, which specify progenitor cells within the developing neural tube. Crucially, this process not only requires the activation of specific fate determinants but also the active repression of alternative fates. While multiple layers of epigenetic regulation—including DNA and histone methylation and chromatin accessibility—govern this repression, their cross-talk and the mechanisms that selectively silence specific genomic loci in a cell-type-dependent manner remain largely elusive.
Deciphering how these repressive mechanisms shape human neuronal development—and how their disruption contributes to NDDs—has long been a challenge. However, recent advances in single-cell transcriptomics, epigenomics, and neural organoid models now provide an unprecedented opportunity to tackle this question. In this project, we will harness these cutting-edge technologies, leveraging cerebellar and spinal organoids that we developed as in vitro models of neural development.
As a molecular entry point, we will focus on PRDM13, a validated alternative fate repressor implicated in pontocerebellar hypoplasia (PCH type 17), a rare NDD. PRDM13 belongs to the PRDM family of chromatin regulators, known to function as sequence-specific remodelers either directly or via interactions with other epigenetic modifiers. Loss-of-function studies in animal models show that PRDM13 ensures the proper commitment of progenitor cells to a GABAergic fate by repressing glutamatergic determinants, in both the cerebellum and spinal cord. These findings support the hypothesis that PRDM13 acts as a sequence-specific epigenetic repressor, guiding cell fate trajectories in a context-dependent manner. However, the full extent of its role—particularly in human neurodevelopment—along with the nature of its chromatin-modulating activity and its sequence-binding specificity, remain unresolved.
Our preliminary results using PRDM13 mutant organoid models demonstrate their potential to capture key regulatory disruptions associated with PRDM13 dysfunction. Using these models and integrating multiple approaches (genetic engineering, single-cell multi-omics, functional epigenomics, and proteomics), we aim to define where and how PRDM13 modulates chromatin states and, consequently, influences individual cell fate trajectories.
This research will provide critical insights into the epigenetic mechanisms that canalize neuronal differentiation. Given the growing recognition of the implication epigenetic dysregulations in NDDs, and the challenges in interpreting non-coding genome variants, our findings will also have broad implications for understanding neurodevelopmental disorders beyond PRDM13-related pathologies.