The methylation status of the embryonic limb skeletal progenitors determines their cell fate in chicken.
Cristina Sanchez-FernandezCarlos Ignacio Lorda-DiezJuan M HurleJuan Antonio MonteroPublished in: Communications biology (2020)
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.
Keyphrases
- dna methylation
- cell death
- genome wide
- cell cycle arrest
- gene expression
- cell fate
- circulating tumor
- cell free
- copy number
- induced apoptosis
- single molecule
- stem cells
- poor prognosis
- mesenchymal stem cells
- transcription factor
- radiation therapy
- magnetic resonance imaging
- signaling pathway
- binding protein
- endoplasmic reticulum stress
- extracellular matrix
- dual energy
- genome wide identification