The HUSH complex controls brain architecture and protocadherin fidelity

Abstract

Fine-tuning of neural connectivity is important for cerebral functions and brain evolution. Protocadherins provide barcodes for neuronal identity as well as synapse formation and expansion of protocadherin cluster genes has been linked to advanced cognitive functions. The tightly controlled stochastic and combinatorial expression of the different protocadherin isoforms in individual neurons provides the molecular basis for neuronal diversity, neuronal network complexity and function of the vertebrate brain. How protocadherins are epigenetically controlled has not yet been fully elucidated. Here we show that the HUSH (human silencing hub) complex containing H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and Microrchidia CW-type zinc finger protein 2 (MORC2), critically controls the fidelity of protocadherin expression. MPP8 and MORC2A are highly expressed in the murine brain and exclusively found in neurons. Genetic inactivation of Mphosph8 (coding for MPP8) or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, MPP8 and MORC2A precisely and selectively suppress the repetitive-like protocadherin gene cluster on mouse chromosome 18 in a H3K9me3-dependent manner, thereby affecting synapse formation. Moreover, we demonstrate that individual MPHOSPH8- or MORC2-deficient neurons in human cerebral organoids express increased numbers of clustered protocadherin isoforms. Our data identify the HUSH complex, previously linked to silencing of repetitive transposable elements, as a key epigenetic regulator of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.

Microrchidia CW-Type Zinc Finger 2, a Chromatin Modifier in a Spectrum of Peripheral Neuropathies

“…They also prevent the synthesis of retroviral envelope proteins that are particularly involved in neurodegeneration (Turelli et al, 2020). Finally, in a Morc2 KO mouse model, the overexpression of the protocadherin cluster has been associated with a loss of neuromuscular functions (Hagelkruys et al, 2021). In the same study, a Mpp8-Morc2 double KO mouse model was shown to develop the same phenotype than the Morc2 KO and the Mpp8 KO mice, suggesting that a common pathway (the HUSH complex) is responsible for the phenotype.…”

“…In mouse, Morc2 expression is dynamic during development with a peak of expression in early phases followed by a decrease during aging (Sancho et al, 2019). Morc2 is highly expressed in the brain, exclusively in neurons, and a Morc2 KO in mice is lethal at embryonic day 13.5 (Hagelkruys et al, 2021). Altogether, these observations suggest a critical role of MORC2 during development especially in the brain.…”

“…MORC2 is also involved in transcriptional repression through H3K9me3 deposition mediated by the HUSH complex. Numerous studies have established the role of MORC2 in controlling the expression of, among others, transposable elements (TEs) (Liu et al, 2017), Kruppel-associated box zinc finger (KZNF) genes (Tchasovnikarova et al, 2015) and more recently the protocadherin cluster (Hagelkruys et al, 2021). Interestingly, all three types of loci have been reported to be independently involved in neurogenesis.…”

The HUSH-SETDB1-MORC2 epigenetic repressor complex restricts herpesvirus infection in association with PML nuclear bodies

“…Given the essential role of MORC2 for the HUSH complex activity 28,43 , this suggests that the HUSH-SETDB1-MORC2 repression complex acts as a major epigenetic regulatory entity to maintain HSV-1 latency in neurons. SETDB1 is known for its major involvement in neurons survival and brain development 44 , and the role of HUSH-MORC2 in developmental aspects of the CNS has recently been put to the limelight 45 . The involvement of the HUSH-SETDB1-MORC2 entity in the acute control, then long-term maintenance, of the latency of a neurotropic virus is thus of particular interest.…”