Ectopic transcription due to inappropriately inherited histone methylation may interfere with the ongoing function of terminally differentiated cells

Abstract

Many human neurodevelopmental disorders are caused byde novomutations in histone modifying enzymes. These patients have craniofacial defects, developmental delay, intellectual disability and behavioral abnormalities, but it remains unclear how the mutations lead to such developmental defects. Here we take advantage of the invariantC. eleganslineage along with a unique double mutant in the H3K4me1/2 demethylase SPR-5/LSD1/KDM1A and the H3K9 methyltransferase MET-2/SETDB1 to address this question. We demonstrate thatspr-5; met-2double mutant worms have a severe chemotaxis defect that is dependent upon the ectopic expression of germline genes in somatic tissues. In addition, by performing single-cell RNAseq, we find that germline genes begin to be ectopically expression widely inspr-5; met-2embryos. However, surprisingly we found thatspr-5; met-2mutants have no somatic lineage defects prior to the 200-cell stage of embryogenesis. This suggests that the altered chemotaxis behavior may be due to ongoing defect in terminally differentiated cells rather than a defect in development. To test this directly, we used RNAi to shut off the ectopic expression of germline genes in L2spr-5; met-2larvae, which have a fully formed nervous system. Remarkably, we find that shutting off the ectopic germline expression rescues normal chemotaxis behavior in the same adult worms that previously had a chemotaxis defect at the L2 stage. This suggests that ongoing ectopic transcription can block normal behavior in a fully intact nervous system. These data raise the possibility that intellectual disability and altered behavior in neurodevelopmental syndromes, caused by mutations in histone modifying enzymes, could be due to ongoing ectopic transcription and may be reversible.