Aicardi–Goutières Syndrome associated mutations of RNase H2B impair its interaction with ZMYM3 and the CoREST histone-modifying complex

Abstract

DNA-RNA hybrids arise in all cell types, and are removed by multiple enzymes, including the trimeric ribonuclease, RNase H2. Mutations in human RNase H2 result in Aicardi–Goutières syndrome (AGS), an inflammatory brain disorder notable for being a Mendelian mimic of congenital viral infection. Previous studies have shown that several AGS-associated mutations of the RNase H2B subunit do not affect trimer stability or catalytic activity and are clustered on the surface of the complex, leading us to speculate that these mutations might impair important interactions of RNase H2 with so far unidentified proteins. In this study, we show that AGS mutations in this cluster impair the interaction of RNase H2 with several members of the CoREST chromatin-silencing complex that include the histone deacetylase HDAC2 and the demethylase KDM1A, the transcriptional regulators RCOR1 and GTFII-I as well as ZMYM3, an MYM-type zinc finger protein. We also show that the interaction is mediated by the zinc finger protein ZMYM3, suggesting that ZMYM3 acts as a novel type of scaffold protein coordinating interactions between deacetylase, demethylase and RNase H type enzymes, raising the question of whether coordination between histone modifications and the degradation of RNA-DNA hybrids may be required to prevent inflammation in humans.

Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

“…The biological role of ZMYM3 is also supportive of disease relevance. ZMYM3 is part of a transcriptional corepressor complex that includes HDAC1, RCOR1 and KDM1A 10,11 . Additional interactors in this complex can include ZMYM2 and REST.…”

“…Additionally, ZMYM3 has since been shown to physically interact with RNASEH2A; variation in RNASEH2A (MIM:606034) has been associated with Aicairdi-Gouteres Syndrome 4 (AGS4, MIM:610333). Specifically, a cluster of pathogenic variants found in AGS4 patients have been shown to disrupt binding of RNAseH to ZMYM3 11 . Residues within the PV-rich domain of ZMYM3 (specifically 862-943) have been shown to be necessary for this interaction.…”

“…Despite this, data from large sequence databases such as gnomAD 9 and TopMed/BRAVO (https://bravo.sph.umich.edu/freeze8/hg38/) do provide critical frequency data from control populations to support (or refute) new XLID associations 6 . ZMYM3 (MIM: 300061) lies on the X chromosome and encodes a member of a transcriptional corepressor complex that includes HDAC1, RCOR1, and KDM1A 10,11 ZMYM3 was originally identified as an XLID candidate gene in a female with a balanced X;13 translocation affecting the 5' UTR of one isoform of ZMYM3 12 . The proband presented with ID, scoliosis, spotty abdominal hypopigmentation, slight facial asymmetry, clinodactyly, and history of a possible febrile seizure at age one year.…”

“…ZMYM3 (MIM: 300061) lies on the X chromosome and encodes a member of a transcriptional corepressor complex that includes HDAC1, RCOR1, and KDM1A 10,11 . ZMYM3 was originally identified as an XLID candidate gene in a female with a balanced X;13 translocation affecting the 5’ UTR of one isoform of ZMYM3 12 .…”

“…Despite this, data from large sequence databases such as gnomAD 9 and TopMed/BRAVO (https://bravo.sph.umich.edu/freeze8/hg38/) do provide critical frequency data from control populations to support (or refute) new XLID associations 6 . ZMYM3 (MIM: 300061) lies on the X chromosome and encodes a member of a transcriptional corepressor complex that includes HDAC1, RCOR1, and KDM1A 10,11 .…”