DZIP1 is a disease-associated epigenetic factor with imprinting function.

We previously identified DZIP1 as an X-inactivation associated factor that could support an epigenetic “reverse” imprinting function in a screen to identify genes that could control activation of the XIC- regulatory non-coding RNA FIRRE. We describe here discovery of DZIP1 as an important disease-associated or disease-contributing factor in humans. DZIP1 expression distinguished the luminal B subtypes from luminal A, basal and HER2+ subtypes, and distinguished the squamous from adenocarcinoma subtypes of non-small cell lung cancer. In most iPSC AD models tested, DZIP1 was activated or silenced. In two autism iPSC models, DZIP1 was activated. In an LRRK2 mutant Parkinson's Disease iPSC model, DZIP1 was again perturbed. DZIP1 is a sub-type specifying factor, on par with homeoboxes in terms of selective pressure it can apply to lineage specification during transformation. The data support an emerging concept of imprinting -based epigenetic dysregulation as a basic underlying factor in human disease; we argue this accounts for or explains (at least in part) “thresholds” or “switches” observed at onset of clinical disease.