Journal Article

Usp16 contributes to somatic stem-cell defects in Down’s syndrome

Haro-Acosta, Veronica, Garner, Craig C., Reddy, Vadiyala M., Clarke, Michael F., Adorno, Maddalena, Mitra, Siddhartha S., Sikandar, Shaheen, Cheshier, Samuel, Ouadah, Youcef, Kuo, Angera, Nicolis di Robilant, Benedetta, Rodriguez, Jacqueline, Quarta, Marco, Qian, Dalong

2013

Overview

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. An analysis of somatic tissues derived from mouse models of Down’s syndrome shows reduced self-renewal capacities in various cell types, with these defects partially dependent on triplication of the Usp16 gene; overexpression and knockout studies in human cells shows that USP16 has a role in Down’s syndrome-related proliferation defects, making this gene an attractive option for further study. Excess Usp16 linked to Down's syndrome People with Down's syndrome have abnormalities in multiple tissues including mental retardation and early ageing. The disease is often the result of full or partial trisomy of chromosome 21, but the molecular mechanisms underlying the observed cellular defects remain largely unknown. An analysis of haematopoietic stem cells in the Down's syndrome mouse model Ts65Dn has revealed a reduced self-renewal associated with the proliferation of cells expressing three copies of the Usp16 gene, which encodes a deubiquitination enzyme involved in chromatin remodelling and cell cycle progression. In a second Down's syndrome mouse model, Ts1Cje, haematopoietic stem cells were not defective. Downregulation of USP16 rescued the functional defects of affected Ts65Dn cells. Overexpression of USP16 in normal human fibroblasts reduced their proliferative capacity and USP16 downregulation partially rescued human Down's syndrome fibroblast proliferation defects. The authors propose that USP16 is a potential target for therapeutics designed to ameliorate the pathologies associated with this syndrome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/532/2118 / 631/532/2118 / Adult Stem Cells - metabolism / Adult Stem Cells - pathology / Animals / Bone marrow / Causes of / Cell Proliferation / Cellular Senescence / Chromosomes, Human, Pair 21 - genetics / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / Disease Models, Animal / Down syndrome / Down Syndrome - genetics / Down Syndrome - metabolism / Down Syndrome - pathology / Epithelium - metabolism / Female / Fibroblasts - cytology / Fibroblasts - metabolism / Fibroblasts - pathology / Gene Dosage / Gene Expression Regulation / Health aspects / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - pathology / Humanities and Social Sciences / Humans / Mammary Glands, Animal - cytology / Mammary Glands, Animal - metabolism / Mice / Molecular Targeted Therapy / multidisciplinary / Neural Stem Cells - metabolism / Neural Stem Cells - pathology / Physiological aspects / Rodents / Science / Stem cells / Transplants & implants / Trisomy - genetics / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - metabolism / Ubiquitin-proteasome system / Ubiquitination