Mini-heterochromatin domains constrain thecis-regulatory impact of SVA transposons in human brain development and disease

Abstract

AbstractSVA retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene-regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here, we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia-parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at theTAF1locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate thecis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increasedTAF1intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized, and their regulatory impact constrained by an innate epigenetic defense system.