Decoding gene repression: how transcription factors and corepressors pioneer chromatin silencing to shape cell identity (360G-Wellcome-329819_Z_25_Z)

Cellular differentiation enables a single genome to give rise to the diverse range of specialised cells required for multicellular life. Transcription factors (TFs) direct the gene expression patterns governing cellular differentiation. TFs bind specific regulatory sequences and recruit chromatin- modifying complexes to regulate expression, with activators and repressors working in concert to canalise cell fate. While the mechanisms by which TFs open chromatin, activate enhancers, and induce expression have been extensively studied, how TFs remodel the chromatin landscape to induce repression remains poorly understood. Using the hematopoietic TF Ikaros as a model, I will elucidate how TFs and corepressors initiate repression during differentiation, and how this process safeguards against malignancy. Ikaros is essential for B-cell differentiation and a tumour suppressor in acute lymphoblastic leukaemia. I discovered that Ikaros acts as a potent repressor that rapidly silences gene expression by dismantling active enhancers. Ikaros interacts with chromatin remodellers and DNA/H3K9 methylation machinery, but how TFs like Ikaros bind and precisely deploy corepressors to disrupt active regulatory networks to drive differentiation remains unclear. This research will identify new TF–corepressor interactions and uncover the molecular mechanisms by which TF-induced repression shapes cell identity and restrains tumourigenesis.