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

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 r

SUBMITTER: Zug R 

PROVIDER: S-EPMC8801891 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature