title: Usp16 contributes to somatic stem-cell defects in Down's syndrome.
abstract: Down's syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Adorno
authors.forename: Shaheen
authors.initials: S
authors.lastname: Sikandar
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.forename: Angera
authors.initials: A
authors.lastname: Kuo
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nicolis Di Robilant
authors.forename: Veronica
authors.initials: V
authors.lastname: Haro-Acosta
authors.forename: Youcef
authors.initials: Y
authors.lastname: Ouadah
authors.forename: Marco
authors.initials: M
authors.lastname: Quarta
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Dalong
authors.initials: D
authors.lastname: Qian
authors.forename: Vadiyala M
authors.initials: VM
authors.lastname: Reddy
authors.forename: Samuel
authors.initials: S
authors.lastname: Cheshier
authors.forename: Craig C
authors.initials: CC
authors.lastname: Garner
authors.forename: Michael F
authors.initials: MF
authors.lastname: Clarke
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000473:pathology; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology*; D014314:Trisomy / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C118778:USP16 protein, human; C584021:Usp16 protein, mouse; D043222:Ubiquitin Thiolesterase
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