Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

Olga Gewartowska; Goretti Aranaz-Novaliches; Paweł S Krawczyk; Seweryn Mroczek; Monika Kusio-Kobiałka; Bartosz Tarkowski; Frantisek Spoutil; Oldrich Benada; Olga Kofroňová; Piotr Szwedziak; Dominik Cysewski; Jakub Gruchota; Marcin Szpila; Aleksander Chlebowski; Radislav Sedlacek; Jan Prochazka; Andrzej Dziembowski

doi:10.1016/j.celrep.2021.109015

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

Cell Rep. 2021 Apr 20;35(3):109015. doi: 10.1016/j.celrep.2021.109015.

Authors

Olga Gewartowska¹, Goretti Aranaz-Novaliches², Paweł S Krawczyk³, Seweryn Mroczek⁴, Monika Kusio-Kobiałka¹, Bartosz Tarkowski³, Frantisek Spoutil⁵, Oldrich Benada⁶, Olga Kofroňová⁶, Piotr Szwedziak⁷, Dominik Cysewski⁸, Jakub Gruchota³, Marcin Szpila³, Aleksander Chlebowski⁸, Radislav Sedlacek⁵, Jan Prochazka⁵, Andrzej Dziembowski⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Laboratory of RNA Biology, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland.
⁵ 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; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the CAS, Prague, Czech Republic.
⁶ Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
⁷ Laboratory of Structural Cell Biology, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland; ReMedy-International Research Agenda Unit, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland.
⁸ Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland.
⁹ 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. Electronic address: adziembowski@iimcb.gov.pl.

PMID: 33882302
DOI: 10.1016/j.celrep.2021.109015

Abstract

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.

Keywords: FAM46A; Nanopore; TENT5A; collagen; direct RNA sequencing; osteoblasts; osteogenesis; osteogenesis imperfecta; poly(A) tail; polyadenylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcification, Physiologic / genetics*
Cell Differentiation
Collagen Type I / genetics
Collagen Type I / metabolism
Collagen Type I, alpha 1 Chain / genetics
Collagen Type I, alpha 1 Chain / metabolism
Disease Models, Animal
Eye Proteins / genetics
Eye Proteins / metabolism
Female
Gene Expression Regulation, Developmental
Humans
Male
Mice
Mice, Knockout
Nerve Growth Factors / genetics
Nerve Growth Factors / metabolism
Nucleotidyltransferases / genetics
Nucleotidyltransferases / metabolism
Osteoblasts / metabolism*
Osteoblasts / pathology
Osteogenesis / genetics*
Osteogenesis Imperfecta / genetics*
Osteogenesis Imperfecta / metabolism
Osteogenesis Imperfecta / pathology
Osteonectin / genetics
Osteonectin / metabolism
Polyadenylation
Polynucleotide Adenylyltransferase / genetics*
Polynucleotide Adenylyltransferase / metabolism
Protein Isoforms / deficiency
Protein Isoforms / genetics
RNA, Messenger / genetics*
RNA, Messenger / metabolism
Sequence Analysis, RNA
Serpins / genetics
Serpins / metabolism
Signal Transduction

Substances

Col1a1 protein, mouse
Col1a2 protein, mouse
Collagen Type I
Collagen Type I, alpha 1 Chain
Eye Proteins
Nerve Growth Factors
Osteonectin
Protein Isoforms
RNA, Messenger
SPARC protein, mouse
Serpins
pigment epithelium-derived factor
Nucleotidyltransferases
Tent5c protein, mouse
Polynucleotide Adenylyltransferase
TENT5A protein, human
Tent5A protein, mouse