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

Date Published: March 19, 2019

Publisher: Public Library of Science

Author(s): Alexander Shapson-Coe, Brenda Valeiras, Christopher Wall, Cristina Rada, Mary Bryk.


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.

Partial Text

Aicardi–Goutières syndrome (AGS) is a rare, largely autosomal-recessive disorder characterised by microcephaly, basal ganglia calcification and elevated levels of lymphocytes and interferon-alpha in the cerebrospinal fluid, with occasional extra-neurological involvement of the liver, spleen and skin [1,2]. AGS usually presents at birth or within the first few months of life, and is strikingly reminiscent of congenital viral infection of the brain, although the failure to find a causative pathogen suggests that AGS may be a disorder of the immune system [2]. The AGS phenotype is thought to result from elevated levels of interferon-alpha, and can be recapitulated by overexpression of interferon-alpha in the murine central nervous system leading to the basal ganglia calcification, angiopathy and astrocytosis seen in AGS patients [3].

The experiments presented here identify RNase H2 as a novel component of the co-repressor of transcription KDM1A/RCOR1/HDAC2 LCH complex, via its interaction with ZMYM proteins ZMYM3 and ZMYM2. ZMYM2 and 3 have been shown to associate with the KDM1A/RCOR1/HDAC2 complex [20], although their precise functions within the complex are not known. CoREST was originally identified as a repressor enforcing the transcriptional silencing of neuronal genes in non-neuronal tissues and neuronal stem cells [24] but it also acts on different lineage-specific genes, for example repressing non-erythroid gene expression in haematopoietic stem cells and pro-inflammatory responses in astrocytes [25] or acting to regulate enhancer activity and transcriptional activation of androgen receptor regulated genes in human prostate cell lines [26]. The multiplicity of functions associated with the CoREST complex are a result of the diverse composition of these multiprotein complexes in different cell types and at different developmental stages, but are generally associated with transcriptional silencing and depend on the core KDM1A/RCOR1/HDAC (LCH) complex and its histone H3 lysine4 and lysine9 demethylase activity and histone deacetylase activities [27].




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