Endogenous retroviruses in genome organization during early embryogenesis

• Applicant: Denes Hnisz, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Developmental Biology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507881362

The 3D organization of the genome plays essential roles in the control of gene expression programs, and many recent studies have focused on the contribution of nuclear proteins to 3D genome organization. Here we propose to investigate the roles of notoriously understudied and abundant repetitive DNA elements that originate from endogenous retroviruses (ERVs) in genome organization in pluripotent stem cells. ERVs are repressed by heterochromatin in stem cells, but are transiently transcribed during embryonic development, and in several disease contexts. Our preliminary data suggest that transcribed ERVs can engage in long-range chromatin contacts with transcribed genes, but the biological roles and importance of these contacts are unknown. In the proposed work, we will investigate the contribution of long-range contacts mediated by heterochromatin-adapter proteins to ERV repression in murine embryonic stem cells; and we will identify the components and molecular mechanisms utilized by transcribed ERVs to mediate long-range chromatin interactions with cellular genes. We will rationally mutagenize the TRIM28 heterochromatin-adapter protein that binds ERVs, and measure genomic interactions and ERV transcription genome-wide in embryonic stem cells. Furthermore, we will systematically perturb transcription factors that bind ERVs, perturb RNA species produced by ERVs, and determine the impact of the perturbations on genome organization and transcription. The results will provide new insights into the contributions of ERVs to 3D genome organization, and ultimately shed new light on the mechanisms transposable elements engage in shaping mammalian genomes on an evolutionary scale.

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