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Developmental disorders caused by haploinsufficiency of transcriptional regulators : a perspective based on cell fate determination

Zug, Roman LU (2022) In Biology Open 11(1).
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Chromatin regulator, Cooperativity, Developmental disorder, Haploinsufficiency, Positive feedback, Transcription factor
in
Biology Open
volume
11
issue
1
publisher
The Company of Biologists Ltd
external identifiers
  • pmid:35089335
  • scopus:85123817326
ISSN
2046-6390
DOI
10.1242/bio.058896
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022. Published by The Company of Biologists Ltd.
id
2807cd76-5c93-4b00-8624-599d476285d9
date added to LUP
2022-02-16 13:10:49
date last changed
2024-09-05 18:51:24
@article{2807cd76-5c93-4b00-8624-599d476285d9,
  abstract     = {{<p>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.</p>}},
  author       = {{Zug, Roman}},
  issn         = {{2046-6390}},
  keywords     = {{Chromatin regulator; Cooperativity; Developmental disorder; Haploinsufficiency; Positive feedback; Transcription factor}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  publisher    = {{The Company of Biologists Ltd}},
  series       = {{Biology Open}},
  title        = {{Developmental disorders caused by haploinsufficiency of transcriptional regulators : a perspective based on cell fate determination}},
  url          = {{http://dx.doi.org/10.1242/bio.058896}},
  doi          = {{10.1242/bio.058896}},
  volume       = {{11}},
  year         = {{2022}},
}