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GeroScience

, Volume 41, Issue 1, pp 39–49 | Cite as

Progerin expression induces a significant downregulation of transcription from human repetitive sequences in iPSC-derived dopaminergic neurons

  • Walter ArancioEmail author
Original Article

Abstract

Repetitive DNA sequences represent about half of the human genome. They have a central role in human biology, especially neurobiology, but are notoriously difficult to study. The purpose of this study was to quantify the transcription from repetitive sequences in a progerin-expressing cellular model of neuronal aging. Progerin is a nuclear protein causative of the Hutchinson–Gilford progeria syndrome that is also incrementally expressed during the normal aging process. A dedicated pipeline of analysis allowed to quantify transcripts containing repetitive sequences from RNAseq datasets oblivious of their genomic localization, tolerating a sufficient degree of mutational noise, all with low computational requirements. The pipeline has been applied to a published panel of RNAseq datasets derived from a well-established and well-described cellular model of aging of dopaminergic neurons. Progerin expression strongly downregulated the transcription from all the classes of repetitive sequences: satellites, long and short interspersed nuclear elements, human endogenous retroviruses, and DNA transposon. The Alu element represented by far the principal source of transcript originating either from repetitive sequences or from canonical coding genes; it was expressed on average at 192,493.5 reads per kilobase million (RPKM) (SE = 21,081.3) in the control neurons and dropped to 43,760.1 RPKM (SE = 5315.0) in the progerin-expressing neurons, being significant downregulated (p = 0.0005). The results highlighted a global perturbation of transcripts derived from repetitive sequences in a cellular model of aging and provided a direct link between progerin expression and alteration of transcription from human repetitive elements.

Keywords

Alu Repetitive sequences Progerin Retrotransposon Satellites 

Abbreviations

HERV

human endogenous retrovirus

HGPS

Hutchinson Gilford Progeria Syndrome

HSAT

high copy satellite

iPSC

induced pluripotent stem cell

iPSC-mDA-GFP

GFP expressing iPSC-derived human midbrain dopamine neurons

iPSC-mDA-GFP-Progerin

GFP-progerin-expressing iPSC-derived human midbrain dopamine neurons

LINE

long interspersed nuclear element

LTR

long terminal repeat

PD

Parkinson’s disease

RPKM

reads per kilobase million

RS

repetitive sequence

SE

standard error

SINE

small interspersed nuclear elements

Notes

Acknowledgements

I want to thank the VICOR’s, Dr. S Genovese, and Prof. A.M. Puglia, Prof. G. Gallo, and all the members of their lab for their help in a difficult period of my personal and professional life.

Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest to disclose, this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors, that the data is not published or submitted elsewhere, and that approval of procedures and approval of the manuscript has been provided by all authors.

Supplementary material

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Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STeBiCeF), Viale delle ScienzeUniversity of PalermoPalermoItaly

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