title: Variant U1 snRNAs are implicated in human pluripotent stem cell maintenance and neuromuscular disease.
abstract: The U1 small nuclear (sn)RNA (U1) is a multifunctional ncRNA, known for its pivotal role in pre-mRNA splicing and regulation of RNA 3' end processing events. We recently demonstrated that a new class of human U1-like snRNAs, the variant (v)U1 snRNAs (vU1s), also participate in pre-mRNA processing events. In this study, we show that several human vU1 genes are specifically upregulated in stem cells and participate in the regulation of cell fate decisions. Significantly, ectopic expression of vU1 genes in human skin fibroblasts leads to increases in levels of key pluripotent stem cell mRNA markers, including NANOG and SOX2. These results reveal an important role for vU1s in the control of key regulatory networks orchestrating the transitions between stem cell maintenance and differentiation. Moreover, vU1 expression varies inversely with U1 expression during differentiation and cell re-programming and this pattern of expression is specifically de-regulated in iPSC-derived motor neurons from Spinal Muscular Atrophy (SMA) type 1 patient's. Accordingly, we suggest that an imbalance in the vU1/U1 ratio, rather than an overall reduction in Uridyl-rich (U)-snRNAs, may contribute to the specific neuromuscular disease phenotype associated with SMA.
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: Pilar
authors.initials: P
authors.lastname: Vazquez-Arango
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.|Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Vowles
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Browne
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.|Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hartfield
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.|Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Hugo J R
authors.initials: HJ
authors.lastname: Fernandes
authors.affiliation: Cedars-Sinai Medical Center, Board of Governors-Regenerative Medicine Institute and Department of Biomedical Sciences, 8700 Beverly Blvd, AHSP A8418, Los Angeles, CA 90048, USA.|iPSC Core, The David and Janet Polak Foundation Stem Cell Core Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Berhan
authors.initials: B
authors.lastname: Mandefro
authors.affiliation: Cedars-Sinai Medical Center, Board of Governors-Regenerative Medicine Institute and Department of Biomedical Sciences, 8700 Beverly Blvd, AHSP A8418, Los Angeles, CA 90048, USA.|iPSC Core, The David and Janet Polak Foundation Stem Cell Core Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Sareen
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: William
authors.initials: W
authors.lastname: James
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.|Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.|Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Cowley
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK shona.murphy@path.ox.ac.uk.
authors.forename: Shona
authors.initials: S
authors.lastname: Murphy
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK dawn.oreilly@path.ox.ac.uk.
authors.forename: Dawn
authors.initials: D
authors.lastname: O'Reilly
mesh_terms: D002478:Cells, Cultured; D005786:Gene Expression Regulation; D000066449:Human Embryonic Stem Cells / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D012342:RNA, Small Nuclear / Q000235:genetics* / Q000378:metabolism; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D012342:RNA, Small Nuclear; C405483:U1 small nuclear RNA