Integrative genomic approaches to understand human cell fate reprogramming in development and genetic diseases

The past decade has been characterized by unprecedented progress in the field of descriptive genomics, increasing the capacity to finely map regulatory regions and DNA sequence variants, which are responsible for the phenotypic differences between individuals as well as disease susceptibility. Recent findings on the control of gene expression programs has had an essential impact on our perception of transcriptional misregulation in pathologic conditions, as many different disorders are due to mutations in regulatory sequences and their cognate transcription factors. Indeed, numerous mendelian diseases are attributable to alterations in transcription factors acting at the node of gene regulatory networks, often responsible for subtle changes at critical moments of cell fate decisions.
Some transcription factors with dominant roles in controlling cell fate decisions are also capable of reprogramming cell states when ectopically expressed, turning somatic cells into stem cells or new cell identities and thus stimulating new research directions into human regenerative medicine. However, the chance to successfully develop patient-tailored therapies is still very limited because reprogramming technologies lack a comprehensive understanding of the molecular processes involved, and manufacturing cells requires knowledge of the exact combination of genes governing the transitions from the starting cell type to the target type. Also, the precise dynamics through which transcription factors regulate cell fate decisions and to what extent associated DNA sequence variants can determine pathogenic effects are still largely unknown. In our lab, we carry out a multifaceted approach that combines a wide range of genomic strategies to significantly advance our understanding of the regulatory logic driving cell fate during human reprogramming. Our ultimate goal is to improve the quality and fidelity of such strategies to unlock the full potential of induced cell fate reprogramming in regenerative medicine therapies.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.