TDP-43 is a genome-wide DNA-binding protein and regulator of snRNA expression

TAR DNA-binding protein 43 (TDP-43) is the major protein component of neuronal inclusions characterizing the adult-onset neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Whereas TDP-43 was originally identified as a DNA-binding protein that bound the HIV-1 trans-activation response (TAR) DNA element, recent work elucidating its role in neurodegenerative disease pathogenesis has largely focused on TDP-43's role as an RNA-binding protein. Here, we demonstrate that in human cells, TDP-43 binds DNA genome-wide, with strong enrichment at small nuclear RNA (snRNA) genes. Moreover, TDP-43 binding to snRNA genes is not dependent on RNA, and the snRNA products of TDP-43-bound sites are incorporated into Smith antigen-containing snRNPs. Furthermore, TDP-43 knockdown increases expression of bound snRNA genes, supporting a role for TDP-43 in the negative regulation of snRNA biogenesis. Finally, ALS-associated missense mutations in the gene encoding TDP-43, TARDBP, reduce binding to snRNA genes. Together, our data suggest that the DNA-binding role of TDP-43 is important in health and in disease, and aberrant TDP-43 binding to snRNA gene loci may alter splicing function in ALS and FTLD-TDP. Overall design: TDP-43 ChIP-seq in HEK293 cells. Input, three independent TDP-43 ChIP replicates, negative control TDP-43 ChIP in the context of TDP-43 knockdown.