Enhancers require an active resetting phase after transcriptional activation
- 1NATIONAL CENTRE FOR BIOLOGICAL SCIENCES, BANGALORE, INDIA
Abstract
Signal-responsive enhancers must activate transcription and then return to a competent but inactive state, yet whether this transition is passive or actively driven has remained unresolved. We define this process as enhancer resetting and identify the androgen receptor (AR) as the factor that executes it as an endogenous response to estrogen signaling, independent of exogenous androgen. As estrogen receptor- (ER) undergoes ligand-induced proteasomal degradation during late-phase signaling, AR progressively accumulates in the nucleus and preferentially occupies highly active, persistent ER enhancers in a transcriptionally silent manner. This late-phase AR binding evicts the pioneer factor FOXA1 from chromatin while preserving baseline accessibility, a handoff mechanism that decouples chromatin openness from active transcription. Conversely, augmenting AR activity by DHT treatment or AR overexpression accelerates FOXA1 eviction, while disrupting AR chromatin binding, either by AR knockdown or a DNA-binding-deficient mutant, prevents it, leaving enhancers in an aberrantly permissive state that drives amplified ER rebinding and transcriptional hyperactivation upon subsequent estrogen stimulation. These findings establish active enhancer resetting as a mechanism safeguarding the fidelity of repeated transcriptional responses. Failure of this mechanism may underlie the transcriptional dysregulation that drives tumor progression and endocrine therapy resistance in ER-positive breast cancer, where estrogen signaling is chronic and cyclic.
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BibTeX
@misc{najar2026enhancers,
title = {{Enhancers require an active resetting phase after transcriptional activation}},
author = {A. H. Najar and R. Mann and S. Indra and D. Soota and P. Kundu and S. Nidharshan and R. N. Vadnala and D. Notani},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.752844},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752844v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Enhancers require an active resetting phase after transcriptional activation
AU - A. H. Najar
AU - R. Mann
AU - S. Indra
AU - D. Soota
AU - P. Kundu
AU - S. Nidharshan
AU - R. N. Vadnala
AU - D. Notani
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.752844
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.752844v1
AB - Signal-responsive enhancers must activate transcription and then return to a competent but inactive state, yet whether this transition is passive or actively driven has remained unresolved. We define this process as enhancer resetting and identify the androgen receptor (AR) as the factor that executes it as an endogenous response to estrogen signaling, independent of exogenous androgen. As estrogen receptor- (ER) undergoes ligand-induced proteasomal degradation during late-phase signaling, AR progressively accumulates in the nucleus and preferentially occupies highly active, persistent ER enhancers in a transcriptionally silent manner. This late-phase AR binding evicts the pioneer factor FOXA1 from chromatin while preserving baseline accessibility, a handoff mechanism that decouples chromatin openness from active transcription. Conversely, augmenting AR activity by DHT treatment or AR overexpression accelerates FOXA1 eviction, while disrupting AR chromatin binding, either by AR knockdown or a DNA-binding-deficient mutant, prevents it, leaving enhancers in an aberrantly permissive state that drives amplified ER rebinding and transcriptional hyperactivation upon subsequent estrogen stimulation. These findings establish active enhancer resetting as a mechanism safeguarding the fidelity of repeated transcriptional responses. Failure of this mechanism may underlie the transcriptional dysregulation that drives tumor progression and endocrine therapy resistance in ER-positive breast cancer, where estrogen signaling is chronic and cyclic.
ER -