Signal-induced enhancer activation requires Ku70 to read topoisomerase1-DNA covalent complexes.
Yuliang TanLu YaoAmir GamlielSreejith J NairHavilah TaylorKenny OhgiAneel K AggarwalMichael G RosenfeldPublished in: Nature structural & molecular biology (2023)
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.
Keyphrases
- transcription factor
- single molecule
- dna damage
- genome wide
- gene expression
- binding protein
- circulating tumor
- drug induced
- public health
- dna methylation
- oxidative stress
- rheumatoid arthritis
- hepatitis b virus
- signaling pathway
- electronic health record
- protein protein
- cell cycle arrest
- deep learning
- artificial intelligence
- blood brain barrier
- quantum dots
- heat shock
- fluorescent probe
- data analysis