TY - JOUR
T1 - Signal-induced enhancer activation requires Ku70 to read topoisomerase1–DNA covalent complexes
AU - Tan, Yuliang
AU - Yao, Lu
AU - Gamliel, Amir
AU - Nair, Sreejith J.
AU - Taylor, Havilah
AU - Ohgi, Kenny
AU - Aggarwal, Aneel K.
AU - Rosenfeld, Michael G.
N1 - Funding Information:
The authors are grateful to J. Hightower for assistance with figure preparation; to M. J. Friedman at UCSD for the plasmids encoding Top1 wt and Y723F mutant and to other members of the Rosenfeld laboratory for generous help throughout this work. M.G.R. was an investigator with the Howard Hughes Medical Institute during this study. This work was supported by grants from National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK018477, RO1DK039949), National Heart, Lung, and Blood Institute (R01HL150521) and National Institute of Neurological Disorders and Stroke (RO1NS034934) to M.G.R., and a grant from National Institute of General Medical Science (R35-GM131780) to A.K.A. S.J.N. is supported by R03DK131250.
Funding Information:
The authors are grateful to J. Hightower for assistance with figure preparation; to M. J. Friedman at UCSD for the plasmids encoding Top1 wt and Y723F mutant and to other members of the Rosenfeld laboratory for generous help throughout this work. M.G.R. was an investigator with the Howard Hughes Medical Institute during this study. This work was supported by grants from National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK018477, RO1DK039949), National Heart, Lung, and Blood Institute (R01HL150521) and National Institute of Neurological Disorders and Stroke (RO1NS034934) to M.G.R., and a grant from National Institute of General Medical Science (R35-GM131780) to A.K.A. S.J.N. is supported by R03DK131250.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85147495744&partnerID=8YFLogxK
U2 - 10.1038/s41594-022-00883-8
DO - 10.1038/s41594-022-00883-8
M3 - Article
C2 - 36747093
AN - SCOPUS:85147495744
SN - 1545-9993
VL - 30
SP - 148
EP - 158
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 2
ER -