Effects of ATRX Deficiency and/or Altered Ubiquitination on Candidate Gene Expression in Hippocampal Tissue from C57BL/6J Mice

Abstract

The autism-risk gene Atrx encodes the chromatin-remodeling protein ATRX, which regulates histone ubiquitination and gene expression. Clariom™ assays were used to determine the effects of ATRX deficiency and ubiquitination disruption on hippocampal transcription in adult male mice. ATRX deficiency and RING1Bi-mediated ubiquitination inhibition resulted in genome-wide downregulation of memory-related genes, which was partially reversed by USP10 inhibition. Candidate genes were selected from Clariom™ assay STRING analysis. RT-qPCR analyses of mRNA levels for Brap, Crh, Gnrh1, Kras, Nr4a1, Pomc, and Prkcd aligned with the Clariom™ assay results. ELISAs revealed altered protein levels of GNRH1, KRAS, and PRKCD (but not NR4A1) in the ATRX-deficient and ubiquitination-disrupted mice. Increased hippocampal KRAS levels correlated with impaired spatial learning and memory in the Morris water maze. These findings highlight potential mechanistic pathways and upstream targets-such as Brap, Crh, Gnrh1, Kras, Nr4a1, Pomc, and Prkcd-for future studies into gene regulation underlying autism-related cognitive dysfunction.