Signal-induced enhancer activation requires Ku70 to read topoisomerase1–DNA covalent complexes
Year: 2023
Type: article
Abstract: Enhancer activation serves as the main mechanism regulating signal-dependent transcriptional programs, ensuring cellular plasticity, yet central questions persist regarding their mechanism of activation. Here, by successfully mapping topoisomerase I-DNA covalent complexes genome-wide, we find that most, if not all, acutely activated enhancers, including those induced by 17β-estradiol, dihydrotestosterone, tumor necrosis factor alpha and neuronal depolarization, are hotspots for topoisomerase I-DNA covalent complexes, functioning as epigenomic signatures read by the classic DNA damage sensor protein, Ku70. Ku70 in turn nucleates a heterochromatin protein 1 gamma (HP1γ)-mediator subunit Med26 complex to facilitate acute, but not chronic, transcriptional activation programs. Together, our data uncover a broad, unappreciated transcriptional code, required for most, if not all, acute signal-dependent enhancer activation events in both mitotic and postmitotic cells.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Funders: Howard Hughes Medical Institute, University of California, San Diego, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G196148165, G2665867018, G3382319324, G3435838258, G379376375, G3800209034, Phase Separation: A New Phase in Decoding Enhancer-dependent Critical Transcriptional Programs by Nuclear Receptors, G651098378, G7398420960, Revealing the roles of HSV1 lytic and latent transcripts in AD pathogenesis and therapy
OpenAlex ID: W4319311472