ArticleBiology open2022
Developmental disorders caused by haploinsufficiency of transcriptional regulators: a perspective based on cell fate determination.
Article in Biology open, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Rethinking 'rare'Journal of Parkinson's disease · 2025Pooled it
- Nonlinearities and Switch-Like Behavior in Gene Expression: From Genetics to Biochemistry and Back.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Analysis of haploinsufficiency in human neural progenitor cells: insights into early molecular effects of autism-related genes.Cell death & disease · 2026Article
- Unveiling a novel role for p19Arf (alternative reading frame) in mESC differentiation toward the pancreatic lineage.Scientific reports · 2026Article
- Curing the brain: in search for new astrocyte-specific therapies.Experimental & molecular medicine · 2026Review
- Enhancer Dynamics for Gene Regulation in the Cardiovascular System.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Density transitions in the regulation of transcription.Molecular cell · 2026Review
- Loss of Twist1 leads to disruption of ciliary length, endocytic vesicle dynamics, and cell-cell junctions during neural tube formation.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Article
- PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias.Nature communications · 2025Article
- Transcriptional regulation as a dose-dependent process: insights from transcription factor tuning.Open biology · 2025Review
- Article
- Novel Gene-Informed Regional Brain Targets for Clinical Screening for Major Depression.Neurology international · 2025Article
- Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders.iScience · 2025Review
- Transcription regulation by biomolecular condensates.Nature reviews. Molecular cell biology · 2025Review
- Why all MODY variants in transcription factor genes are dominantly inherited.Frontiers in genetics · 2025Article
- Regulatory properties of transcription factors with diverse mechanistic function.PLoS computational biology · 2024Article
- Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development.Nature neuroscience · 2024Article
- Coactivator condensation drives cardiovascular cell lineage specification.Science advances · 2024Article
- Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders.Orphanet journal of rare diseases · 2024Article
- Phenotypic heterogeneity in human genetic diseases: ultrasensitivity-mediated threshold effects as a unifying molecular mechanism.Journal of biomedical science · 2023Review
Corrections and comments
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Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease. This article has an associated Future Leader to Watch interview with the author of the paper.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.