Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, NEURAL CREST DEVELOPMENT, PHENOTYPIC ROBUSTNESS, DNA-BINDING, STEM-CELLS, SOX9, ENHANCER, VARIANT, DISEASE, HAPLOINSUFFICIENCY, DISCOVERY, Humans, SOX9 Transcription Factor, Pierre Robin Syndrome, Gene Expression Regulation, Regulatory Sequences, Nucleic Acid, Phenotype, C14/20/081#55685098, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

Abstract:

Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.