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Abstract
Digits shape is sculpted by interdigital programmed cell death during limb development. Here, we show that DNA breakage in the periphery of 5-methylcytosine nuclei foci of interdigital precursors precedes cell death. These cells showed higher genome instability than the digit-forming precursors when exposed to X-ray irradiation or local bone morphogenetic protein (BMP) treatments. Regional but not global DNA methylation differences were found between both progenitors. DNA-Methyl-Transferases (DNMTs) including DNMT1, DNMT3B and, to a lesser extent, DNMT3A, exhibited well-defined expression patterns in regions destined to degenerate, as the interdigital tissue and the prospective joint regions. Dnmt3b functional experiments revealed an inverse regulation of cell death and cartilage differentiation, by transcriptional regulation of key genes including Sox9, Scleraxis, p21 and Bak1, via differential methylation of CpG islands across their promoters. Our findings point to a regulation of cell death versus chondrogenesis of limb skeletal precursors based on epigenetic mechanisms.
Highlights
Digits shape is sculpted by interdigital programmed cell death during limb development
An outstanding question in the understanding of embryonic sculpting processes is whether epigenetic mechanisms sensitize the skeletal progenitors to DNA damage signals that are harmless to cells committed to chondrogenesis
To investigate whether the biological effect of Dnmt3b gene silencing was related to methylation catalysis, we examined the effect of chemical inhibition of DNA methyltransferase activity with 5-azacytidine[21]
Summary
Digits shape is sculpted by interdigital programmed cell death during limb development. An outstanding question in the understanding of embryonic sculpting processes is whether epigenetic mechanisms sensitize the skeletal progenitors to DNA damage signals that are harmless to cells committed to chondrogenesis. We show that prior to the onset of cell death, interdigital cells bear higher genome instability than the digit-forming precursors This difference was associated with a differential expression of DNA-Methyl-Transferases in digit, joint primordia and interdigital tissues. Consistent with the pattern of gene expression, functional experiments in the micromass culture assay revealed an intense influence of DNA-Methyl-Transferase 3b promoting cell death and inhibiting chondrogenesis These findings were associated with changes in the methylation status of the CpG islands of the promoter of key genes including Sox[9], Scleraxis, p21, and Bak[1]
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