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

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, howand 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.

Automated summary

This study proposes a hypothesis that haploinsufficiency of transcriptional regulators leads to developmental disorders due to disrupted bistability in the gene regulatory network. The hypothesis explains the inherent property of dosage sensitivity in fate decisions and the role of positive feedback and TF cooperativity. The framework provides a mechanistic explanation and new insights into human disease.