Structuring the genome through phase-separated transcriptional condensates

• Applicant: Denes Hnisz, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Developmental Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422774126

Much recent work indicates that the 3D organization of the genome plays essential roles in the control of gene expression programs that underlie the cellular identity of all cell types in complex metazoans. Here we propose a model that gene expression in turn has a significant contribution to structuring the genome. We have recently discovered that gene transcription involves a liquid-liquid phase separation event that underlies the formation of transcriptional condensates of unusual features. Phase separation is typically driven by multivalent, low affinity interactions between intrinsically disordered regions (IDRs) in proteins, and numerous transcription factors that occupy enhancer elements contain sequence portions that resemble IDRs. In Aim 1, we will investigate the hypothesis that transcription factor IDRs are able to drive the formation of nuclear condensates that facilitate long distance DNA interactions in mammalian cells. Furthermore, human genetics data indicate that a large number of human developmental disorders are caused by mutations in transcriptional regulators, and that these mutations tend to occur in the predicted IDRs of those transcriptional regulators. In Aim 2, we will test the hypothesis that such disease-associated IDR mutations impair the ability of transcriptional regulators to form nuclear condensates, and consequently disrupt long-range DNA interactions. Our studies will provide new insights into the molecular processes that regulate genome structure, and into the mechanistic relationship between genome structure and gene expression. The results of this work we believe will ultimately facilitate the design of strategies that interfere with IDR-driven genome structuring as a therapeutic approach.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2202: Spatial Genome Architecture in Development and Disease