Reciprocal Regulation of Transcription for Protein-Coding and Non-Coding Alu Transcripts by TDP-43

Abstract

TAR DNA binding protein of 43 kDa (TDP-43) is a ubiquitously expressed RNA and DNA binding protein with reported functions in transcription, processing, transport, and translation of RNA transcripts. A vast majority of studies of TDP-43 pertain to its involvement in RNA splicing and RNA processing following transcription. However, to date, only a handful of studies have explored TDP-43’s role as a regulator of transcription. The present study for the first time characterizes the effects of TDP-43 depletion on transcription genome-wide in human cells. We employ global nuclear run-on sequencing (GRO-Seq) to identify sites of active transcription throughout the genome and change of transcription at these sites following depletion of TDP-43. We compare these GRO-Seq results to publicly available data from other genome-wide sequencing experiments to determine the contribution of TDP-43-dependent changes in transcription of genes to their mRNA levels, as well as potential gene targets regulated by TDP-43 through association with chromatin. Our analysis uncovers a potential role of TDP-43 in regulating transcription of Alu elements, a kind of short transposable element-derived repeat element. We found depletion of TDP-43 leads to a drastic increase in transcription of Alu elements throughout the genome, particularly within actively transcribed genes. We also found a general decrease in transcription of protein-coding genes that correlates with the density of actively transcribing Alu elements located within genes. Our results reveal a novel role of TDP-43 as a transcriptional repressor of Alu elements.