UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
| Autor: | Juan M. Hurle, Carlos I. Lorda-Diez, Juan A. García-Porrero, Cristina Sanchez-Fernandez, Juan A. Montero |
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| Přispěvatelé: | Universidad de Cantabria |
| Rok vydání: | 2019 |
| Předmět: |
Cell death
Cancer Research Programmed cell death Cellular differentiation Ubiquitin-Protein Ligases Immunology Apoptosis Cartilage metabolism Chick Embryo Biology Article Mesoderm Cellular and Molecular Neuroscience Mice Animals RNA Small Interfering lcsh:QH573-671 Cellular Senescence Regulation of gene expression Cartilage development lcsh:Cytology Scleraxis Gene Expression Regulation Developmental Cell Differentiation Extremities Cell Biology DNA Methylation Chondrogenesis Embryo Mammalian Embryonic stem cell Cell biology Fibroblast Growth Factors Cartilage bcl-2 Homologous Antagonist-Killer Protein DNA methylation S Phase Cell Cycle Checkpoints RNA Interference Signal Transduction |
| Zdroj: | Cell Death Dis. 2019 10(5):347 UCrea Repositorio Abierto de la Universidad de Cantabria Universidad de Cantabria (UC) Cell Death and Disease, Vol 10, Iss 5, Pp 1-14 (2019) Cell Death & Disease |
| Popis: | The primordium of the limb contains a number of progenitors far superior to those necessary to form the skeletal components of this appendage. During the course of development, precursors that do not follow the skeletogenic program are removed by cell senescence and apoptosis. The formation of the digits provides the most representative example of embryonic remodeling via cell degeneration. In the hand/foot regions of the embryonic vertebrate limb (autopod), the interdigital tissue and the zones of interphalangeal joint formation undergo massive degeneration that accounts for jointed and free digit morphology. Developmental senescence and caspase-dependent apoptosis are considered responsible for these remodeling processes. Our study uncovers a new upstream level of regulation of remodeling by the epigenetic regulators Uhrf1 and Uhrf2 genes. These genes are spatially and temporally expressed in the pre-apoptotic regions. UHRF1 and UHRF2 showed a nuclear localization associated with foci of methylated cytosine. Interestingly, nuclear labeling increased in cells progressing through the stages of degeneration prior to TUNEL positivity. Functional analysis in cultured limb skeletal progenitors via the overexpression of either UHRF1 or UHRF2 inhibited chondrogenesis and induced cell senescence and apoptosis accompanied with changes in global and regional DNA methylation. Uhrfs modulated canonical cell differentiation factors, such as Sox9 and Scleraxis, promoted apoptosis via up-regulation of Bak1, and induced cell senescence, by arresting progenitors at the S phase and upregulating the expression of p21. Expression of Uhrf genes in vivo was positively modulated by FGF signaling. In the micromass culture assay Uhrf1 was down-regulated as the progenitors lost stemness and differentiated into cartilage. Together, our findings emphasize the importance of tuning the balance between cell differentiation and cell stemness as a central step in the initiation of the so-called ?embryonic programmed cell death? and suggest that the structural organization of the chromatin, via epigenetic modifications, may be a precocious and critical factor in these regulatory events. Funding: We thank Montse Fernandez Calderon, Susana Dawalibi, and Sonia Perez Mantecon, for excellent technical assistance. This work was supported by a Grant (BFU2017-84046-P) from the Spanish Science and Innovation Ministry to J.A.M. |
| Databáze: | OpenAIRE |
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