Authors
Reiner A Veitia, James A Birchler
Published in
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. Volume 40. Issue 16. Pages e72232. Aug 31, 2026.
Abstract
Many developmental and physiological outcomes depend on transcriptional thresholds or switches. The transcriptional output, ultimately measured as mature RNA, is determined by a series of molecular steps that can introduce thresholds, bottlenecks, or amplification mechanisms. Their combination can convert quantitative changes in regulator abundance into more-than-proportional changes in mature RNA production. Such nonlinear, S-shaped/sigmoidal input-output relationships may account, at least in part, for the haploinsufficiency (HI) of transcription factors (TFs) and chromatin regulators. Here, we link genetic evidence for dosage sensitivity to biochemical nonlinearity in the context of transcription regulation. Without aiming to be exhaustive, we discuss several sources of sigmoidicity, such as classical cooperative DNA binding and transcriptional synergy. We also analyze how chromatin factors, three-dimensional nuclear organization, and transcriptional condensates can generate thresholds. In addition, we explore the roles of epigenetic hysteresis and molecular memory. Finally, at the systems level, we consider how nonlinearities can emerge from regulatory networks that convert graded changes in regulator abundance into stable alternative states. Overall, this paper supports the view that HI of TFs and chromatin regulators does not rely on a single mechanism. Rather, HI is a phenotypic consequence of the disruption of diverse molecular and network architectures that translate dosage perturbations into discrete biochemical and phenotypic outcomes.
PMID:
42631548
Bibliographic data and abstract were imported from PubMed on 24 Aug 2026.
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