Enhancer buffering protects dosage-sensitive housekeeping genes during vulnerable developmental transitions
- 1Stanford University School of Medicine
Abstract
Housekeeping genes maintain robust expression across cell types despite dynamic transcription factor fluctuations, yet their haploinsufficiency is associated with many tissue-specific developmental disorders. To understand this paradox, we focus on TCOF1, a broadly expressed regulator of rRNA synthesis, whose haploinsufficiency causes Treacher Collins syndrome (TCS). We show that transitional cranial neural crest cells (tCNCC) undergoing mesenchymal specification exhibit extreme dosage-sensitivity to TCOF1, but not to RNA polymerase I, explaining both cellular origins of TCS and prevalence of TCOF1 mutations in the disease. To maintain robust expression, TCOF1 deploys CNCC-specific enhancers that buffer against fluctuations in promoter-regulating factors, converting sensitive expression responses into threshold-protected outputs. Systematic promoter-enhancer coupling experiments demonstrate this principle generalizes across many dosage-sensitive housekeeping genes, whose promoters operate near saturation and only reveal their enhancer-dependency under suboptimal conditions. Thus, enhancers play a unique role at housekeeping promoters: rather than amplifying expression, they ensure its robustness during vulnerable developmental transitions.
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BibTeX
@misc{ni2026enhancer,
title = {{Enhancer buffering protects dosage-sensitive housekeeping genes during vulnerable developmental transitions}},
author = {C. Ni and L. Ichino and T. Swigut and J. Wysocka},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.29.741571},
url = {https://www.biorxiv.org/content/10.64898/2026.07.29.741571v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Enhancer buffering protects dosage-sensitive housekeeping genes during vulnerable developmental transitions
AU - C. Ni
AU - L. Ichino
AU - T. Swigut
AU - J. Wysocka
PY - 2026
DA - 2026/07/29
PB - bioRxiv
DO - 10.64898/2026.07.29.741571
UR - https://www.biorxiv.org/content/10.64898/2026.07.29.741571v2
AB - Housekeeping genes maintain robust expression across cell types despite dynamic transcription factor fluctuations, yet their haploinsufficiency is associated with many tissue-specific developmental disorders. To understand this paradox, we focus on TCOF1, a broadly expressed regulator of rRNA synthesis, whose haploinsufficiency causes Treacher Collins syndrome (TCS). We show that transitional cranial neural crest cells (tCNCC) undergoing mesenchymal specification exhibit extreme dosage-sensitivity to TCOF1, but not to RNA polymerase I, explaining both cellular origins of TCS and prevalence of TCOF1 mutations in the disease. To maintain robust expression, TCOF1 deploys CNCC-specific enhancers that buffer against fluctuations in promoter-regulating factors, converting sensitive expression responses into threshold-protected outputs. Systematic promoter-enhancer coupling experiments demonstrate this principle generalizes across many dosage-sensitive housekeeping genes, whose promoters operate near saturation and only reveal their enhancer-dependency under suboptimal conditions. Thus, enhancers play a unique role at housekeeping promoters: rather than amplifying expression, they ensure its robustness during vulnerable developmental transitions.
ER -