Developmental disorders caused by haploinsufficiency of transcriptional regulators : a perspective based on cell fate determination
(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.
(Less)
- author
- Zug, Roman LU
- organization
- publishing date
- 2022-01-15
- 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
- 2024-09-19 19:58:01
@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}},
}