Chromatin architecture at susceptible gene loci in cerebellar Purkinje cells characterizes DNA damage-induced neurodegeneration

Young Don Kwak, Timothy I. Shaw, Susanna M. Downing, Ambika Tewari, Aditi, Hongjian Jin, Yang Li, Lavinia C. Dumitrache, Sachin Katyal, Kamran Khodakhah, Helen R. Russell, Peter J. McKinnon

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The pathogenesis of inherited genome instability neurodegenerative syndromes remains largely unknown. Here, we report new disease-relevant murine models of genome instability-driven neurodegeneration involving disabled ATM and APTX that develop debilitating ataxia. We show that neurodegeneration and ataxia result from transcriptional interference in the cerebellum via aberrant messenger RNA splicing. Unexpectedly, these splicing defects were restricted to only Purkinje cells, disrupting the expression of critical homeostatic regulators including ITPR1, GRID2, and CA8. Abundant genotoxic R loops were also found at these Purkinje cell gene loci, further exacerbating DNA damage and transcriptional disruption. Using ATAC-seq to profile global chromatin accessibility in the cerebellum, we found a notably unique chromatin conformation specifically in Purkinje chromatin at the affected gene loci, thereby promoting susceptibility to DNA damage. These data reveal the pathogenic basis of DNA damage in the nervous system and suggest chromatin conformation as a feature in directing genome instability-associated neuropathology.

Original languageEnglish (US)
Article numbereabg6363
JournalScience Advances
Volume7
Issue number51
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • General

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