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Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair.

Developmental cell | 2018

Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.

Pubmed ID: 29920279 RIS Download

Mesh terms: Animals | Cell Differentiation | Chromatin | Chromatin Assembly and Disassembly | DNA Helicases | DNA-Binding Proteins | Histone Methyltransferases | Histone-Lysine N-Methyltransferase | Mice | Mice, Knockout | Myelin Sheath | Nerve Fibers, Myelinated | Nuclear Proteins | Oligodendroglia | Rats | Rats, Sprague-Dawley | Transcription Factors

Additional research tools detected in this publication

Antibodies used in this publication

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SAM format (tool)

RRID:SCR_012093

A generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms.

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MACS (tool)

RRID:SCR_013291

An algorithm for identifying transcript factor binding sites. MACS captures the influence of genome complexity to evaluate the significance of enriched ChIP regions, and MACS improves the spatial resolution of binding sites through combining the information of both sequencing tag position and orientation. MACS can be easily used for ChIP-Seq data alone, or with control sample with the increase of specificity.

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Anti-O4, clone 81 (also referred to in the literature as mAB O4) antibody (antibody)

RRID:AB_94872

This monoclonal antibody targets O4 clone 81 (also referred to in the literature as mAB O4)

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CHD8 antibody (antibody)

RRID:AB_10859797

This polyclonal antibody targets CHD8 antibody

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Cleaved Caspase-3 (Asp175) Antibody (antibody)

RRID:AB_2341188

This polyclonal antibody targets Cleaved Caspase-3 (Asp175)

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Trimethyl-Histone H3 (Lys4) antibody (antibody)

RRID:AB_1977252

This polyclonal antibody targets Synthetic peptide corresponding to residues surrounding and including trimethlyated Lys 4 of Histone H3. Epitope Trimethylated (Lys4), This antibody only detects Histone H3 when trimethylated on Lysine 4.

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CD140a antibody (antibody)

RRID:AB_397117

This monoclonal antibody targets CD140a

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MBP (C-16) antibody (antibody)

RRID:AB_648798

This polyclonal antibody targets MBP (C-16)

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Human SOX10 Affinity Purified Polyclonal Ab antibody (antibody)

RRID:AB_442208

This polyclonal antibody targets Human SOX10 Affinity Purified Ab

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CHD8 Antibody (antibody)

RRID:AB_890577

This polyclonal antibody targets CHD8

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CHD7 (D3F5) Rabbit mAb antibody (antibody)

RRID:AB_11220431

This monoclonal antibody targets CHD7 (D3F5) Rabbit mAb

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Rabbit Anti-Green Fluorescent Protein (GFP) Polyclonal Antibody, Unconjugated (antibody)

RRID:AB_221569

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Anti-Myelin Basic Protein antibody (antibody)

RRID:AB_11213157

This polyclonal antibody targets Myelin Basic Protein

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Anti-NeuN antibody (antibody)

RRID:AB_2298772

This monoclonal antibody targets NeuN

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c-Myc (9E10) antibody (antibody)

RRID:AB_627268

This monoclonal antibody targets c-Myc (9E10)

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Anti-SOX10 antibody [EPR4007-104] (antibody)

RRID:AB_2721184

This monoclonal antibody targets SOX10

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GFAP Monoclonal Antibody (2.2B10) (antibody)

RRID:AB_2532994

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GraphPad Prism (tool)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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SAMTOOLS (tool)

RRID:SCR_002105

Software tool for manipulating alignments in SAM format for storing nucleotide sequence alignment, including sorting, merging, indexing and generating alignments in per position format. Parts that are relevant to genetic analysis include SNP and indel callings.

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RRID:SCR_003199

Software package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.

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Bowtie (tool)

RRID:SCR_005476

Software tool for aligning short DNA sequences to the human genome. Bowtie 2 supports gapped, local, and paired end alignment modes.

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CG-4 (cell line)

RRID:CVCL_0210

Cell line CG-4 is aFinite cell line with a species of origin Rattus norvegicus

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HEK293T/17 (cell line)

RRID:CVCL_1926

Cell line HEK293T/17 is aTransformed cell line with a species of origin Homo sapiens

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ToppCluster (tool)

RRID:SCR_001503

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MEME Suite - Motif-based sequence analysis tools (tool)

RRID:SCR_001783

Suite of motif-based sequence analysis tools to discover motifs using MEME, DREME (DNA only) or GLAM2 on groups of related DNA or protein sequences; search sequence databases with motifs using MAST, FIMO, MCAST or GLAM2SCAN; compare a motif to all motifs in a database of motifs; associate motifs with Gene Ontology terms via their putative target genes, and analyze motif enrichment using SpaMo or CentriMo. Source code, binaries and a web server are freely available for noncommercial use.

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HOMER (tool)

RRID:SCR_010881

Software tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.

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R Project for Statistical Computing (tool)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.

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