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

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.