The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination

Abstract

Several key transcription factors and coregulators important to peripheral nerve myelination have been identified, but the contributions of specific chromatin remodeling complexes to peripheral nerve myelination have not been analyzed. Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. Previous studies have shown Chd4 interacts with Nab (NGFI-A/Egr-binding) corepressors, which are required for Early growth response 2 (Egr2/Krox20), to direct peripheral nerve myelination by Schwann cells. In this study, we examined the developmental importance of the NuRD complex in peripheral nerve myelination through the generation of conditional Chd4 knockout mice in Schwann cells (Chd4loxP/loxP; P0-cre). Chd4 conditional null mice were found to have delayed myelination, radial sorting defects, hypomyelination, and the persistence of promyelinating Schwann cells. Loss of Chd4 leads to elevated expression of immature Schwann cell genes (Id2, c-Jun, and p75), and sustained expression of the promyelinating Schwann cell gene, Oct6/Scip, without affecting the levels of Egr2/Krox20. Furthermore, Schwann cell proliferation is upregulated in Chd4 null sciatic nerve. In vivo ChIP studies reveal recruitment of Chd4 and another NuRD component, Mta2, to genes that are positively and negatively regulated by Egr2 during myelination. Taken together, these results underscore the necessity of Chd4 function to guide proper terminal differentiation of Schwann cells and implicate the NuRD chromatin remodeling complex as a requisite factor in timely and stable peripheral nerve myelination.

Transcriptional and Epigenetic Regulation of Oligodendrocyte Development and Myelination in the Central Nervous System

“…The CHD family member, CHD4, reportedly regulates myelination in the PNS (Hung et al 2012). CHD4 conditional mutant mice show a delay in myelination and an increase of immature Schwann cell proliferation.…”

Schwann cells and their transcriptional network: Evolution of key regulators of peripheral myelination

“…Nab proteins interact among others with the chromodomain helicase DNA-binding protein 4 (Chd4) that is part of the NuRD chromatin-remodeling complex (Srinivasan et al, 2006). Interestingly, Schwann cells in conditional Chd4 mouse mutants are transiently arrested at the promyelinating stage even though Sox10 and Krox20 are expressed (Hung et al, 2012). Nab proteins may thus provide a link between Krox20 and NuRD complex as a further chromatin remodeling complex with functional relevance for Schwann cell differentiation (Fig.…”

Architects of the genome: CHD dysfunction in cancer, developmental disorders and neurological syndromes

“…We found that Chd5-compromised mice have severe behavioral phenotypes and aberrant dendritic arborization (Mills, unpublished). A de novo mutation in CHD4 was reported in 1/109 patients with epileptic encephalopathy [109], and conditional disruption of Chd4 specifically within Schwann cells leads to abnormal motor co-ordination and hind limb reflexes [116]. While more supporting human genetic data are needed, these functional data in model organisms and preliminary reports in humans suggest that perturbation of CHD4, CHD5 and CHD6 might also play important roles in neurological dysfunction.…”

“…In addtion, Chd4 is essential for polycomb-mediated inhibition of astroglial differentiation through its interaction with Ezh2 and suppression of genes that induce the astrogenic lineage [128]. Chd4 also interacts with Nab corepressors to direct Schwann cell mediated peripheral nerve myelination, and conditional ablation of Chd4 in Schwann cells leads to delayed myelination, radial sorting defects, hypomyelination and deregulation of promyelinating Schwann cells [116]. In addition, Chd4 is required for expression of CD4 (CD4 molecule) and T-cell development [129], and CHD4 forms a complex with GATA3 (GATA-binding protein 3) to simultaneously activate transcription of Th2 cytokines and to repress transcription of the Th1 cytokine IFNG (interferon, γ) to establish T helper 2 cell identity [130].…”

“…Autoantibodies against CHD4 are detected in 10–30% of human patients with dermatomyositis [132]. While human genetic data implicating CHD4 alterations in neurologic diseases are currently limited, ablation of Chd4 in Schwann cells leads to abnormal motor co-ordination and hind limb reflexes [116], suggesting that CHD4 could affect development of all three types of diseases. Altogether, these findings define deregulation of CHD proteins as a common culprit for three main categories of human diseases, and also indicate shared mechanisms underlying the pathogenesis for the different disease syndromes.…”