Architecture and evolutionary conservation of <i>Xenopus tropicalis</i> osteoblast-specific regulatory regions shed light on bone diseases and early skeletal evolution
Bibliographic record
Abstract
Abstract Understanding the genetic mechanisms underpinning the differentiation of osteoblasts, the bone producing cells, has far reaching implications for skeletal diseases and evolution. To this end, it is crucial to characterize osteoblastic regulatory landscape in a diverse array of distantly-related vertebrate species. By comparing of the ATAC-seq profile of Xenopus tropicalis ( Xt ) osteoblasts to liver, heart and lung control tissues, we identified 524 promoters and 6,750 distal regions whose chromatin is specifically open in osteoblasts. Nucleotide composition, Gene Ontology, and RNA-Seq confirmed that the identified elements correspond to bona fide osteogenic transcriptional enhancers, and TFBS enrichment revealed a well-conserved regulatory logic with mammals. Amongst the 357 Xt osteoblast-specific enhancers aligning to homologous human loci, 127 map to regions annotated as enhancers. Phenotype predictions based on the genes neighbouring these conserved enhancers are tightly related to impaired skeletal development. In addition, six conserved enhancers are located at loci associated to craniosynostosis ( mx2 , tcf12 ), osteopoikilosis ( lemd3 ), osteopenia ( gorab ), skeletal dysplasia ( flnb ) and craniofacial abnormalities ( gpc4 ). From an evolutionary perspective, the elephant shark genome aligns to 53 Xt osteoblast-specific enhancers that are also conserved and annotated as enhancers in humans, revealing an ancestral osteogenic role for the ATOH8, IRX3, NFAT, NFIB and MEF2C transcription factors, as well as for the FGF, IHH and BMP/TGFb signalling pathways. As the absence of bone in sharks is a derived feature, we propose that, in this lineage, the osteogenic regulatory network has been maintained for its function in odontoblasts. Our data argues in favour of a common origin for dentine and bone, and provides a glimpse into the key regulatory elements and upstream activators that drove the formation of an ancient type of mineralized tissue in the vertebrates that inhabited the oceans more than 460 million years ago. Author Summary During animal embryogenesis, distinct type of tissues are formed and assembled, resulting in an integrated, functional organism. During this process, cells must make important decisions, which largely rely on an accurate use of their genetic material. Here, we have studied how the genome “knows” that it must participate to the formation of the bone tissue in a frog animal model. We therefore identified important genomic regions that are involved in driving the expression of genes involved in the formation of a mineralized skeleton. On the one hand, we show that some of these regions are also present in humans, and, therefore, skeletal pathologies could be studied in the frog model at a genetic level. On the other hand, we also identify regions that are present in the genome of a shark, which allows us to propose an evolutionary framework for the early evolutionary origin of the vertebrate skeleton.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".