Laboratory of RNA Biology, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109 Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland.
Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
Cell Rep. 2021 Apr 20;35(3):109015. doi: 10.1016/j.celrep.2021.109015.
Osteoblasts orchestrate bone formation through the secretion of type I collagen and other constituents of the matrix on which hydroxyapatite crystals mineralize. Here, we show that TENT5A, whose mutations were found in congenital bone disease osteogenesis imperfecta patients, is a cytoplasmic poly(A) polymerase playing a crucial role in regulating bone mineralization. Direct RNA sequencing revealed that TENT5A is induced during osteoblast differentiation and polyadenylates mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in osteogenesis, increasing their expression. We postulate that TENT5A, possibly together with its paralog TENT5C, is responsible for the wave of cytoplasmic polyadenylation of mRNAs encoding secreted proteins occurring during bone mineralization. Importantly, the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects. Thus, we report a biologically relevant posttranscriptional regulator of collagen production and, more generally, bone formation.
成骨细胞通过分泌 I 型胶原和基质中的其他成分来调控骨形成，而羟基磷灰石晶体就在这些基质上矿化。在这里，我们发现 TENT5A 是一种细胞质 poly(A) 聚合酶，其突变存在于先天性骨病成骨不全症患者中，在调控骨矿化过程中发挥着关键作用。直接 RNA 测序显示，TENT5A 在成骨细胞分化过程中被诱导表达，并对编码 Col1α1、Col1α2 和其他参与成骨的分泌蛋白的 mRNA 进行多聚腺苷酸化修饰，从而增加其表达。我们推测，TENT5A（可能与其同源物 TENT5C 一起）负责在骨矿化过程中发生的编码分泌蛋白的 mRNA 的细胞质多聚腺苷酸化波。重要的是，Tent5a 敲除（KO）小鼠表现出骨脆性和骨骼矿化不足的表型，这是由于胶原缺陷的数量和质量所致。因此，我们报告了一种对胶原蛋白产生具有生物学意义的转录后调控因子，更广泛地说，对骨形成具有生物学意义的转录后调控因子。
