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Precise modulation of transcription factor levels identifies features underlying dosage sensitivity.

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.

SUBMITTER: Naqvi S

PROVIDER: S-EPMC10181932 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Precise modulation of transcription factor levels identifies features underlying dosage sensitivity.

Naqvi Sahin S Kim Seungsoo S Hoskens Hanne H Matthews Harold S HS Spritz Richard A RA Klein Ophir D OD Hallgrímsson Benedikt B Swigut Tomek T Claes Peter P Pritchard Jonathan K JK Wysocka Joanna J

Nature genetics 20230406 5

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 ...[more]

PMID: 37024583

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Project description:Copy number changes in protein-coding genes are detrimental if the consequent changes in protein concentrations disrupt essential cellular functions. The dosage sensitivity of transcription factor (TF) genes is particularly interesting because their products are essential in regulating the expression of genetic information. From four recently curated data sets of dosage-sensitive genes (genes with conserved copy numbers across mammals, ohnologs, and two data sets of haploinsufficient genes), we compiled a data set of the most reliable dosage-sensitive (MRDS) genes and a data set of the most reliable dosage-insensitive (MRDIS) genes. The MRDS genes were those present in all four data sets, while the MRDIS genes were those absent from any one of the four data sets and with the probability of being loss of function-intolerant (pLI) values < 0.5 in both of the haploinsufficient gene data sets. Enrichment analysis of TF genes among the MRDS and MRDIS gene data sets showed that TF genes are more likely to be dosage-sensitive than other genes in the human genome. The nuclear receptor family was the most enriched TF family among the dosage-sensitive genes. TF families with very few members were also deemed more likely to be dosage-sensitive than TF families with more members. In addition, we found a certain number of dosage-insensitive TFs. The most typical were the Krüppel-associated box domain-containing zinc-finger proteins (KZFPs). Gene ontology (GO) enrichment analysis showed that the MRDS TFs were enriched for many more terms than the MRDIS TFs; however, the proteins interacting with these two groups of TFs did not show such sharp differences. Furthermore, we found that the MRDIS KZFPs were not significantly enriched for any GO terms, whereas their interacting proteins were significantly enriched for thousands of GO terms. Further characterizations revealed significant differences between MRDS TFs and MRDIS TFs in the lengths and nucleotide compositions of DNA-binding sites as well as in expression level, protein size, and selective force.

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Precise modulation of transcription factor levels identifies features underlying dosage sensitivity.

Publications

Precise modulation of transcription factor levels identifies features underlying dosage sensitivity.

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