Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Curr Opin Neurobiol. 2019 May 28;59:59–68. doi: 10.1016/j.conb.2019.04.010

Regulation of Neuronal Connectivity in the Mammalian Brain by Chromatin Remodeling

Jared V Goodman a,b, Azad Bonni a,*
PMCID: PMC6879819  NIHMSID: NIHMS1530358  PMID: 31146125

Summary

Precise temporal and spatial control of gene expression is essential for brain development. Besides DNA sequence-specific transcription factors, epigenetic factors play an integral role in the control of gene expression in neurons. Among epigenetic mechanisms, chromatin remodeling enzymes have emerged as essential to the control of neural circuit assembly and function in the brain. Here, we review recent studies on the roles and mechanisms of the chromodomain-helicase-DNA-binding (Chd) family of chromatin remodeling enzymes in the regulation of neuronal morphogenesis and connectivity in the mammalian brain. We explore the field through the lens of Chd3, Chd4, and Chd5 proteins, which incorporate into the nucleosome remodeling and deacetylase (NuRD) complex, and the related proteins Chd7 and Chd8, implicated in the pathogenesis of intellectual disability and autism spectrum disorders. These studies have advanced our understanding of the mechanisms that regulate neuronal connectivity in brain development and neurodevelopmental disorders of cognition.

Control of gene transcription is dependent on the chromatin state of the cell. As prime effectors of chromatin state changes, epigenetic factors are ideally suited to drive long-lasting changes in genetic programs and regulate large-scale transcriptional alterations in neurons upon exposure to extrinsic cues [1].

The enzymatic activities of epigenetic regulators include post-translational modification of histones, DNA methylation, and nucleosome remodeling. Nucleosome remodeling encompasses ATP-dependent changes in nucleosome spacing, density, or subunit composition [2]. Nucleosomes represent the basic building blocks of chromatin, each comprising an octamer of the histone proteins H2A, H2B, H3, and H4 wrapped by ~147 base pairs of DNA [3]. The canonical histone subunits of nucleosomes may be exchanged for histone variants such as H2A.x, H2A.z, and H3.3 [4]. Altering the positioning or structure of nucleosomes may modulate the accessibility of transcription factors to genomic DNA sequences or recruit additional epigenetic regulators [5,6].

Numerous chromatin remodelers are encoded in the mammalian genome, including members of the Swi/Snf, Chd, Iswi, and Ino80 families of ATP-dependent helicases [2]. Five of nine members of the Chd family proteins—Chd1, Chd2, Chd4, Chd7, and Chd8—have been implicated in neurodevelopmental disorders of cognition including intellectual disability and autism spectrum disorders [7–18], attesting to their critical role in brain development. Here, we review recent advances toward understanding the functions and mechanisms of remodeling enzymes in neuronal connectivity from the perspective of the nucleosome remodeling and deacetylase (NuRD) complex-associated Chd proteins Chd3, Chd4, and Chd5 and the related proteins Chd7 and Chd8. Studies of the Brg/Brm-associated factors (BAF) and other chromatin remodeling complexes have also advanced our understanding of the regulation of neuronal development and plasticity, a topic that has been reviewed elsewhere [19,20].

Roles of NuRD-associated Chd proteins in neuronal connectivity

One of three closely related Chd proteins—Chd3, Chd4, and Chd5—forms the core ATPase subunit of the NuRD complex. Distinguishing the NuRD complex from other chromatin remodeling complexes is the presence of a second enzymatic activity of a class I histone deacetylase—Hdac1 or Hdac2. The scaffold proteins Mbd2/3, Rbap46/48, Mta1/2/3, and Gatad2a/b additionally form in the NuRD complex [21–26]. Among these proteins, Mbd3 may be required for assembly of the NuRD complex in cells [27], though this function has not been validated in neurons. NuRD complex proteins bind genomic regulatory sites directly via intrinsic DNA-binding capacity and interaction with post-translationally modified histone proteins as well as indirectly upon recruitment by transcription factors [28]. The NuRD complex has been implicated in transcriptional repression [28], but the complete suite of NuRD-dependent epigenomic functions remains to be elucidated.

Distinct functions of NuRD-associated Chd proteins in cortical neurogenesis

Chd3, Chd4, and Chd5 have unique expression patterns in the developing mouse brain. In the rodent cerebral cortex, Chd4 is robustly expressed in both neural precursors and mature neurons [29]. Conditional knockout of Chd4 in neural precursors in the mouse cerebral cortex leads to early cell-cycle exit and depletion of these cells, thereby causing microcephaly [29]. In contrast to Chd4, Chd3 and Chd5 are expressed predominantly in postmitotic neurons in the cortical plate, in particular in deep layers of the cerebral cortex [29,30]. Knockdown of Chd3 and Chd5 by RNAi triggers distinct phenotypes in the cerebral cortex. Depletion of Chd5 results in buildup of multipolar neurons in the subventricular and intermediate zones [29,30], whereas depletion of Chd3 leads to accumulation of neurons in the deep cortical layers [29]. These results suggest that Chd3, Chd4, and Chd5 may regulate distinct phases of cortical neurogenesis (Fig. 1a).

Figure 1: Chromatin remodeling enzymes coordinate distinct phases of neuronal differentiation.

Figure 1:

Open in a new tab

(A) Distinct phases of cortical neuron differentiation are governed by chromatin remodeling enzymes. Proliferation of cortical neuron precursors requires Chd4. Whereas Chd3 promotes early differentiation and migration of cortical neuron precursors, Chd5 promotes migration of cortical neurons into upper layers of the cortex. Cortical neuron precursor proliferation and differentiation may be also subject to control by Chd8. (B) Distinct chromatin remodeling enzymes control granule neuron differentiation in the cerebellum. Whereas the initiation of granule neuron differentiation requires Chd7, Chd4 orchestrates afferent and efferent connectivity of granule neurons in the internal granule and molecular layers in the cerebellum. VZ, ventricular zone. IZ/SVZ, intermediate zone/subventricular zone. CP, cortical plate. Sup., superficial. EGL, external granule layer. ML, molecular layer. PCL, Purkinje cell layer. IGL, internal granule layer.

Chd4 drives efferent and afferent neuronal connectivity via distinct epigenetic mechanisms

Insights into the functions and mechanisms of Chd4 and the NuRD complex in neuronal connectivity have come largely from studies of granule neurons in the rodent cerebellum. Granule neuron precursors proliferate and differentiate into postmitotic neurons in the external granule layer (EGL) [31]. Subsequently, granule neurons migrate inward, through the molecular layer and past Purkinje cells, into the internal granule layer (IGL), where they mature [31] (Fig. 1b). A whole host of transcriptional regulators have been demonstrated to regulate distinct stages of granule neuron development [31–42], attesting to the crucial role of cell-intrinsic transcriptional control of neuronal morphogenesis and connectivity. These studies also raise the fundamental question of whether regulation of transcription by global epigenetic factors might coordinate neuronal connectivity.

The Chd4/NuRD complex assembles in the cerebellum at a time when granule neurons undergo synapse formation [43]. Accordingly, conditional knockout and knockdown studies have uncovered a critical function for Chd4 and other components of the NuRD complex in granule neuron parallel fiber presynaptic differentiation in the cerebellar cortex in vivo [43]. Electron microscopic analyses of mice in which the Chd4 gene is selectively disrupted in granule neurons reveal reduced number of parallel fiber/Purkinje cell synapses [43]. These developmental deficits are associated with profound impairments of neurotransmission at this synapse [43]. Thus, Chd4 and the NuRD complex drive the formation of functional granule neuron synapses onto Purkinje neurons (Figs. 1–2).

Figure 2: Molecular control of granule neuron differentiation by Chd7 and Chd4.

Figure 2:

Open in a new tab

Chd7 regulates the genomic binding of TopIIb and long gene expression in granule neuron precursors, thus controlling differentiation of these cells. Chd4 decommissions promoters of developmental genes, silencing them and thereby driving granule neuron parallel fiber/Purkinje cell synapse formation. In contrast, Chd4 deposits histone variant H2A.z at promoters of activity genes and shuts of their transcription, leading to dendrite elimination and sparse encoding.

A mechanism by which Chd4 drives presynaptic differentiation has been elucidated. Genome-wide studies of the cerebellum in conditional Chd4 knockout and control mice shows that Chd4 represses a program of ~200 developmentally regulated genes [43]. The histone tail modifications H3K27ac, H3K9/14ac, and H3K4me3, associated with transcriptional activation, are specifically upregulated at promoters of the ~200 genes in the cerebellum upon conditional Chd4 knockout [43]. A targeted in vivo RNAi screen of Chd4-target genes suggests that downregulation of specific genes mediates Chd4-induced presynaptic differentiation in the cerebellar cortex [43]. These findings show that Chd4 and the NuRD complex trigger silencing of developmentally regulated genes via promoter decommissioning and thereby drive synapse differentiation (Fig. 2).

Although Chd4 decommissions the promoters of ~200 genes in granule neurons, Chd4 occupies thousands of actively transcribed gene promoters in granule neurons in the cerebellum [44], raising the questions of how and whether Chd4 might regulate the much larger set of actively transcribed genes. Besides alterations of histone tail modifications, exchange of H2A with the histone variant H2A.z at gene promoters regulates transcription [45]. Strikingly, conditional knockout of Chd4 in the mouse cerebellum reduces H2A.z enrichment at promoters of actively transcribed genes independently of changes in histone tail marks [44], suggesting that Chd4 drives deposition of H2A.z at promoters of actively transcribed genes in the brain (Fig. 2).

In gene ontology analyses, genes regulated by the Chd4/H2A.z epigenetic pathway encode proteins engaged in intracellular signaling and phosphorylation cascades [44], providing a clue that this pathway might be dynamically regulated. Consistent with this prediction, transcriptomic and epigenomic analyses in primary granule neurons and in the mouse cerebellum in vivo have revealed that Chd4 loads H2A.z at the promoters of neuronal activity-dependent immediate early genes (IEGs) specifically during the shutoff, but not activation, phase of transcription and thereby shuts off their transcription [44]. These results define the Chd4/H2A.z link as a novel epigenetic mechanism that actively shuts off IEG transcription, with potential implications for understanding the control of gene expression in response to extrinsic cues beyond neuronal activity and the nervous system.

The Chd4/H2A.z epigenetic pathway and consequent shutoff of activity-dependent genes bears important consequences for neuronal morphogenesis and connectivity. Analyses of neuronal morphology in conditional Chd4 knockout mice and upon expression of a panel of Chd4-regulated activity genes show that Chd4-dependent shutoff of activity genes triggers the pruning of granule neuron dendrites during brain development [44]. Remarkably, two-photon microscopy analyses of awake-behaving mice uncover a crucial role for Chd4 in the control of sparse encoding of granule neurons to sensorimotor stimuli [44].

Collectively, studies of Chd4 in the developing cerebellum have revealed that whereas Chd4 drives efferent connectivity via promoter decommissioning of developmental genes, a Chd4/H2A.z epigenetic pathway shuts off activity-dependent transcription and thereby drives afferent connectivity (Fig. 2). The requirement for Chd4 in the establishment of neuronal connectivity during development has lasting effects on cerebellar functions, as conditional Chd4 knockout mice have profound impairments in associative motor learning in adulthood [44].

Chd4 mutations in intellectual disability

Consistent with the growing evidence that Chd4 plays a critical role in the regulation of neuronal connectivity during development, recent studies have identified numerous de novo variants in Chd4 among patients with intellectual disability [12–14]. Chd4 variants cause missense mutations [12–14], suggesting that, besides reduced activity, modulation of the biochemical functions of Chd4 might lead to neuropathology. Supporting this possibility, different endometrial cancer-associated Chd4 missense mutations impair or stimulate the nucleosome remodeling activity of Chd4 in vitro [46]. Missense mutations in Chd4 might also influence proteins that recruit Chd4 to genomic loci. Mutations of three such proteins, Gatad2b, Mbd3, and ADNP, are also associated with neurodevelopmental disorders [47–50]. Intriguingly, unlike Gatad2b and Mbd3, ADNP recruits Chd4 to genomic loci in a NuRD-independent manner [51]. Deregulation of Chd4 activity may thus contribute to the pathogenesis of neurodevelopmental disorders of cognition via alterations in NuRD-dependent and -independent actions.

Biological functions of Chd7 and Chd8 in neuronal connectivity

In addition to Chd4, several other Chd family proteins are associated with neurodevelopmental disorders. Among these proteins, Chd7 and Chd8 functions have been the subject of scrutiny in recent years.

Chd7 organizes neuronal differentiation

Mutations in Chd7 cause CHARGE syndrome, a clinically heterogeneous multi-system disorder, which features coloboma of the eye, heart defects, atresia of the choanae, retardation of growth or development, genital or urinary defects, and ear anomalies or deafness [15]. Blindness, deafness, cranial nerve abnormalities, and developmental delay are highly penetrant [52]. A large proportion of CHARGE patients display intellectual disability [52].

Cellular studies show that Chd7 contributes to terminal differentiation in neurogenic niches in the brain. Conditional deletion of Chd7 in cerebellar granule neuron precursors leads to cerebellar hypoplasia secondary to failure of cell cycle exit and higher death rates in these cells [53] (Fig. 1b). Loss of Chd7 in the developing otocyst causes cochlear hypoplasia and failure to form the semicircular canals and cristae [54]. Conditional loss of Chd7 in adult neurogenic niches of the lateral ventricle subventricular zone and hippocampal subgranular zone impairs neurogenesis [55]. Thus, Chd7 plays a conserved role in organizing terminal differentiation of neurons.

Chd7 may promote neuronal differentiation by activating transcription. Chd7 appears to predominantly occupy distal regulatory elements in several cell types including mESCs and granule neuron precursors [53,56]. Members of the polybromo-associated BAF (PBAF) chromatin remodeling complex interact with Chd7 in human ESC-derived neural crest cells, perhaps at distal regulatory elements, and hence synergistically promote neural crest cell migration in Xenopus embryos [57].

Chd7 also interacts with the DNA gyrase topoisomerase lib (TopIIb) in cell lines and in the adult cerebellum [53]. Topoisomerase function has emerged as critical for transcription of long genes in neurons [58]. Pharmacological inhibition of TopII enzymatic activity partially phenocopies the effect of conditional knockout of Chd7 on gene expression in primary granule neuron precursors [53]. In addition, conditional knockout of Chd7 alters the genome-wide occupancy of TopIIb in primary granule neuron precursors [53]. These data suggest that Chd7 and TopIIb might cooperate to activate long gene expression in the nervous system (Fig. 2).

Chd8 regulates brain size and behavior

Recent advances in sequencing approaches have also identified numerous de novo variants in Chd8 in individuals with sporadic autism spectrum disorders [9,10,16–18]. Depletion of Chd8 in mice results in phenotypes relevant to the clinicopathological features of patients with heterozygous Chd8 null mutations [59–65]. Mice carrying a heterozygous null allele of the Chd8 gene display macrocephaly or megalencephaly [59,61,62,64]. High-resolution MRI scans of megalencephalic mice have demonstrated associated increases in the size of brain structures including the cerebral cortex, amygdala, and hippocampus, but some structures such as the deep cerebellar nuclei are decreased in size [61].

Heterozygous Chd8 mice display abnormal behaviors including in domains of sociability and anxiety. The exact behavioral phenotypes exhibited by these mice vary depending on the study [59–62,64]. Layered on this phenotypic complexity is the sexual dimorphism observed among certain Chd8 mutant mice. In particular, male but not female Chd8+/N2373K mice display abnormal behavior throughout development including anxiety-like maternal-seeking behaviors [60]. Sexually dimorphic changes in synaptic inputs in the hippocampus have been also observed in these mice, which are associated with sex-specific changes in gene expression [60].

In spite of behavioral heterogeneity in Chd8 mutant mice, common themes on Chd8 function have emerged in studies of these mice. Chd8 binds promoters of active genes and some enhancer regions in diverse cell types including mESCs, human induced pluripotent stem cell (iPSC)-derived neural precursor cells, and the brain [64,66,67]. Knockdown or heterozygous knockout of Chd8 deregulates expression of genes encoding chromatin modifiers and RNA processing proteins [59–64,66,68,69], suggesting that Chd8 may operate at the apex of a regulatory gene network in the mouse brain. Deregulated genes upon Chd8 loss also are associated with risk of autism [59–64,66,68,69]. Thus, loss of Chd8 activity might contribute to the pathogenesis of autism spectrum disorders via alterations of autism-associated gene networks.

Chd7 and Chd8 orchestrate distinct phases of oligodendrocyte differentiation

Besides the differentiation of neurons, recent studies have unveiled functions for Chd7 and Chd8 in the control of oligodendrocyte differentiation (Fig. 3). Notably, MRI of the brain in CHARGE syndrome patients and autism patients carrying a null Chd8 allele reveals reduction in white matter volume [65,70]. Consistent with these findings, conditional loss of Chd7 or Chd8 in oligodendrocyte precursors in mice impairs myelination in the brain [65,70].

Figure 3: Molecular control of oligodendrocyte differentiation by Chd7 and Chd8.

Figure 3:

Open in a new tab

Chd8 interacts with MLL complex members Ash21 and Wdr5 and controls chromatin accessibility and H3K4me3 in oligodendrocyte precursors, causing proliferation of these cells. Chd7 interacts with Sox10 to control gene expression, ensuring proper differentiation of oligodendrocytes.

Conditional knockout of Chd8 impairs proliferation of oligodendrocyte precursors in the spinal cord [65]. Genomic studies show widespread loss of chromatin accessibility and decreased enrichment of H3K4me3 at gene promoters in oligodendrocyte precursors upon Chd8 knockout [65]. Chd8 interacts with mixed-lineage leukemia (MLL) histone methyltransferase complex proteins Ash2l and Wdr5 in cells, which stimulate H3K4 methylation [65]. Accordingly, pharmacological inhibition of H3K4 demethylation increases the number of mature oligodendrocytes in conditional Chd8 knockout mice [65]. These results suggest that Chd8 might couple increased accessibility to histone tail methylation to promote proliferation of oligodendrocyte precursors (Fig. 3).

Conditional knockout of Chd7 in oligodendrocyte precursors impairs the survival of these cells and maturation of oligodendrocytes [70,71]. Chd7 interacts with the transcription factor Sox10, which shares genomic sites with Chd7 in differentiating oligodendrocytes [70]. Accordingly, knockdown of Sox10 or Chd7 reduces expression of several lineage-defining transcripts in differentiating oligodendrocytes [70]. Collectively, these results suggest Chd7 collaborates with Sox10 to drive oligodendrocyte differentiation (Fig. 3).

Perspectives

Chromatin remodeling by the Chd family of proteins has emerged in recent years as a major epigenetic mechanism that regulates brain development. Studies of the NuRD-associated Chd proteins Chd3, Chd4, and Chd5, and the related Chd proteins Chd7 and Chd8 have provided novel insights into the functions and mechanisms of chromatin remodeling enzymes in brain development and neurodevelopmental disorders of cognition.

A key concept arising from studies of Chd proteins in the nervous system is that different chromatin remodeling enzymes may be dedicated to distinct phases of nervous system development (Figs. 1–2). Whereas Chd4 regulates proliferation of neural precursors, Chd7 controls terminal neuronal differentiation of neural precursors [29,53]. Likewise, whereas Chd3 and Chd5 coordinate distinct stages of neuron migration, Chd4 orchestrates efferent and afferent neuronal connectivity [29,43,44]. Chd8 may also contribute to proliferation and differentiation of neural precursors [59,61,63]. It will be interesting to explore whether developmental stage-specific functions of different Chd proteins are coordinated with distinct transcription factors, which control specific stages of neuronal differentiation [31–42].

Distinct phases of oligodendrocyte differentiation may also be governed by different chromatin remodeling enzymes (Fig. 3). Whereas Chd8 regulates oligodendrocyte precursor proliferation, Chd7 controls oligodendrocyte differentiation [65,70]. It will be interesting to characterize the functions of other Chd proteins in glial cells.

As advances have come from studies of Chd proteins in neuronal development, these insights have also raised fundamental questions. We know little if anything about how the different Chd proteins are regulated in the brain. It will be important to characterize the relationship between specific extrinsic cues, intracellular signaling cascades, and Chd proteins in the developing brain.

What might distinct Chd subunits confer to the biochemical functions of the NuRD complex during brain development? Chd3, Chd4 or Chd5 incorporation may recruit the complex to distinct sites on the genome. Distinct Chd proteins within the NuRD complex might additionally confer different biochemical activities on the nucleosome. Supporting this possibility, Chd4 seems to preferentially slide nucleosomes, whereas Chd5 may promote nucleosome destabilization [72].

How does Chd4 decommission the promoters of developmentally regulated genes? It is unclear whether NuRD-associated Hdac½ activity directly deacetylates H3K27 and H3K9/14 at the promoters of these genes. Interestingly, the histone demethylase Lsd1, which acts on H3K4 and H3K9, associates with the NuRD complex and represses transcription in murine embryonic stem cells (mESCs) [73,74]. Thus, Lsd1 might contribute to the ability of Chd4 and the NuRD complex to silence genes and drive synapse differentiation in the brain.

How does Chd4 promote the deposition of H2A.z at the promoters of activity-dependent genes? Chd4 might directly promote H2A.z incorporation into the nucleosome or cooperate with the chromatin remodeling enzymes SRCAP or EP400, which deposit H2A.z into nucleosomes [75,76]. The chromatin remodeling enzyme Ino80 evicts H2A.z from gene promoters in yeast, raising the question of whether Chd4 promotes H2A.z deposition by inhibiting Ino80 activity [77].

Does Chd4 regulate H2A.z deposition in other brain regions? The turnover of H2A.z at activity genes has been implicated in the control of memory formation in the mouse hippocampus and prefrontal cortex. In the mouse hippocampus, H2A.z is evicted from numerous gene promoters following contextual fear consolidation [78,79]. Remarkably, knockdown of H2A.z in the CA1 region of the hippocampus or medial prefrontal cortex improves fear memory formation [79]. Whether Chd4 controls H2A.z turnover in these brain regions and consequently formation of fear memory remains to be addressed.

How might Chd7 and TopIIb collaborate to regulate long gene expression? TopII is thought to support gene transcription by relieving DNA supercoils produced during transcription [58,80]. Chromatin remodeling enzymes may also induce DNA supercoils through nucleosome sliding [81,82]. It would be interesting to determine if TopIIb might relieve supercoils generated by Chd7-dependent nucleosome sliding to coordinate granule neuron differentiation.

Might Chd8 couple accessibility to H3K4me3 in neurons? Conditional knockout of MLL complex enzymes Kmt2a and Kmt2b in the mouse hippocampus impairs memory formation, suggesting a role for MLL complex activity in adaptive responses of the brain [83,84]. Exploring the functional relationship between Chd8 and the MLL complex in neurons might uncover new roles for Chd8 in brain function.

Chromatin remodeling enzymes are major effectors of changes in chromatin state. Although advances have been made, many aspects of chromatin remodeling enzyme function remain poorly understood. Improved understanding of chromatin remodeling will contribute to elucidating fundamental principles of brain development as well as help to explain how mutations in chromatin remodeling enzymes contribute to neurodevelopmental disorders of cognition.

Highlights.

  • Chd chromatin remodeling enzymes govern distinct phases of neuronal connectivity

  • Chd4 orchestrates afferent and efferent neuronal connectivity via distinct mechanisms

  • Chd7 activates transcription to promote neuron and oligodendrocyte differentiation

  • Chd8 controls brain size and oligodendrocyte precursor proliferation

Acknowledgements

We thank Yue Yang, Tomoko Yamada, and members of the Bonni laboratory for thoughtful discussion and critical reading of the manuscript. Supported by National Institutes of Health grants NS041021 (AB) and HD094447 (JVG) as well as the Mathers Foundation (AB).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosures

The authors declare no conflict of interest.

References

  • 1.Gallegos DA, Chan U, Chen LF, West AE: Chromatin Regulation of Neuronal Maturation and Plasticity. Trends Neurosci 2018, 41:311–324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Clapier CR, Iwasa J, Cairns BR, Peterson CL: Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol 2017, 18:407–422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Zhou K, Gaullier G, Luger K: Nucleosome structure and dynamics are coming of age.Nat Struct Mol Biol 2019, 26:3–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Soshnev AA, Josefowicz SZ, Allis CD: Greater Than the Sum of Parts: Complexity of the Dynamic Epigenome. Mol Cell 2016, 62:681–694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Voss TC, Hager GL: Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat Rev Genet 2014, 15:69–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Lai WKM, Pugh BF: Understanding nucleosome dynamics and their links to gene expression and DNA replication. Nat Rev Mol Cell Biol 2017, doi: 10.1038/nrm.2017.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Pilarowski GO, Vernon HJ, Applegate CD, Boukas L, Cho MT, Gurnett CA, Benke PJ, Beaver E, Heeley JM, Medne L, et al. : Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. J Med Genet 2018, 55:561–566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Kim YJ, Khoshkhoo S, Frankowski JC, Zhu B, Abbasi S, Lee S, Wu YE, Hunt RF: Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory. Neuron 2018, 100:1180–1193. e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, et al. : Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012, 485:246–250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.O’Roak BJ, Stessman HA, Boyle EA, Witherspoon KT, Martin B, Lee C, Vives L, Baker C, Hiatt JB, Nickerson DA, et al. : Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat Commun 2014, 5:1–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, et al. : Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 2013, 45:825–830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Sifrim A, Hitz M-P, Wilsdon A, Breckpot J, Turki SH Al, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, et al. : Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet 2016, 48:1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Weiss K, Terhal PA, Cohen L, Bruccoleri M, Irving M, Martinez AF, Rosenfeld JA, Machol K, Yang Y, Liu P, et al. : De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms. Am J Hum Genet 2016, 99:934–941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.McRae JF, Clayton S, Fitzgerald TW, Kaplanis J, Prigmore E, Rajan D, Sifrim A, Aitken S, Akawi N, Alvi M, et al. : Prevalence and architecture of de novo mutations in developmental disorders. Nature 2017, 542:433–438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Vissers LELM, Van Ravenswaaij CMA, Admiraal R, Hurst JA, De Vries BBA, Janssen IM, Van Der Vliet WA, Huys EHLPG, De Jong PJ, Hamel BCJ, et al. : Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004, 36:955–957. [DOI] [PubMed] [Google Scholar]
  • 16.Devlin B, Boone BE, Levy SE, Lihm J, Buxbaum JD, Wu Y, Lewis L, Han Y, Boerwinkle E, Gibbs RA, et al. : Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012, 485:242–246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, et al. : Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders. Science (80-) 2012, 338:1619–1622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C, Heilbut A, Ernst C, Hanscom C, Rossin E, Lindgren AM, et al. : Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 2012, 149:525–537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Son EY, Crabtree GR: The role of BAF (mSWI/SNF) complexes in mammalian neural development. Am J Med Genet Part C Semin Med Genet 2014, 166:333–349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Sokpor G, Xie Y, Rosenbusch J, Tuoc T: Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders. Front Mol Neurosci 2017, 10:1–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W: NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell 1998, 2:851–861. [DOI] [PubMed] [Google Scholar]
  • 22.Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D: The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 1998, 95:279–289. [DOI] [PubMed] [Google Scholar]
  • 23.Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL: Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 1998, 395:917–921. [DOI] [PubMed] [Google Scholar]
  • 24.Hendrich B, Bird A: Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 1998, 18:6538–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Brackertz M, Boeke J, Zhang R, Renkawitz R: Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3.J Biol Chem 2002, 277:40958–40966. [DOI] [PubMed] [Google Scholar]
  • 26.Feng Q, Cao R, Xia L, Erdjument-Bromage H, Tempst P, Zhang Y: Identification and functional characterization of the p66/p68 components of the MeCP1 complex. Mol Cell Biol 2002, 22:536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Kaji K, Caballero IM, MacLeod R, Nichols J, Wilson V a, Hendrich B: The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol 2006, 8:285–292. [DOI] [PubMed] [Google Scholar]
  • 28.Allen HF, Wade PA, Kutateladze TG: The NuRD architecture. Cell Mol Life Sci 2013, 70:3513–3524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Nitarska J, Smith JG, Sherlock WT, Hillege MMG, Nott A, Barshop WD, Vashisht AA, Wohlschlegel JA, Mitter R, Riccio A: A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development. Cell Rep 2016, 17:1683–1698. [DOI] [PMC free article] [PubMed] [Google Scholar]; * This article reveals that Chd3, Chd4, and Chd5 regulate sequential phases of cortical neuron development, suggesting that these remodeling enzymes play distinct biological roles in brain differentiation.
  • 30.Egan CM, Nyman U, Skotte J, Streubel G, Turner S, O’Connell DJ, Rraklli V, Dolan MJ, Chadderton N, Hansen K, et al. : CHD5 is required for neurogenesis and has a dual role in facilitating gene expression and polycomb gene repression. Dev Cell 2013, 26:223–236. [DOI] [PubMed] [Google Scholar]
  • 31.de la Torre-Ubieta L, Bonni A: Transcriptional Regulation of Neuronal Polarity and Morphogenesis in the Mammalian Brain. Neuron 2011, 72:22–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Yamada T, Yang Y, Huang J, Coppola G, Geschwind DH, Bonni A: Sumoylated MEF2A Coordinately Eliminates Orphan Presynaptic Sites and Promotes Maturation of Presynaptic Boutons. J Neurosci 2013, 33:4726–4740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Gaudillière B, Konishi Y, de la Iglesia N, Yao G, Bonni A: A CaMKII-NeuroD Signaling Pathway Specifies Dendritic Morphogenesis. Neuron 2004, 41:229–241. [DOI] [PubMed] [Google Scholar]
  • 34.Puram SV, Bonni A: Cell-intrinsic drivers of dendrite morphogenesis. Development 2013, 140:4657–4671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Chen X, Chanda A, Ikeuchi Y, Zhang X, Goodman JV, Reddy NC, Majidi SP, Wu DY, Smith SE, Godec A, et al. : The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain.J Neurosci 2019, 39:44–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Huynh MA, Ikeuchi Y, Netherton S, de la Torre-Ubieta L, Kanadia R, Stegmüller J, Cepko C, Bonni S, Bonni A: An Isoform-Specific SnoN1-FOXO1 Repressor Complex Controls Neuronal Morphogenesis and Positioning in the Mammalian Brain. Neuron 2011, 69:930–944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.de la Torre-Ubieta L, Gaudilliere B, Yang Y, Ikeuchi Y, Yamada T, DiBacco S, Stegmuller J, Schuller U, Salih DA, Rowitch D, et al. : A FOXO-Pak1 transcriptional pathway controls neuronal polarity. Genes Dev 2010, 24:799–813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Ikeuchi Y, Stegmuller J, Netherton S, Huynh MA, Masu M, Frank D, Bonni S, Bonni A: A SnoN-Ccd1 Pathway Promotes Axonal Morphogenesis in the Mammalian Brain. J Neurosci 2009, 29:4312–4321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Ramos B, Gaudilliere B, Bonni A, Gill G: Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation. Proc Natl Acad Sci 2007, 104:9882–9887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Lasorella A, Stegmüller J, Guardavaccaro D, Liu G, Carro MS, Rothschild G, de la Torre-Ubieta L, Pagano M, Bonni A, Iavarone A: Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 2006, 442:471–474. [DOI] [PubMed] [Google Scholar]
  • 41.Stegmüller J, Konishi Y, Huynh MA, Yuan Z, DiBacco S, Bonni A: Cell-Intrinsic Regulation of Axonal Morphogenesis by the Cdh1-APC Target SnoN. Neuron 2006, 50:389–400. [DOI] [PubMed] [Google Scholar]
  • 42.Shalizi A, Gaudillière B, Yuan Z, Stegmüller J, Shirogane T, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A: A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 2006, 311:1012–7. [DOI] [PubMed] [Google Scholar]
  • 43.Yamada T, Yang Y, Hemberg M, Yoshida T, Cho HY, Murphy JP, Fioravante D, Regehr WG, Gygi SP, Georgopoulos K, et al. : Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain. Neuron 2014, 83:122–134 [DOI] [PMC free article] [PubMed] [Google Scholar]; ** In this article, the authors uncover the first function and mechanism for Chd4 and the NuRD complex in the nervous system, revealing that Chd4 and the NuRD complex drive granule neuron efferent connectivity in the cerebellar cortex by decommissioning and thereby silencing the promoters of a set of developmental genes.
  • 44.Yang Y, Yamada T, Hill KK, Hemberg M, Reddy NC, Cho HY, Guthrie AN, Oldenborg A, Heiney SA, Ohmae S, et al. : Chromatin remodeling inactivates activity genes and regulates neural coding. Science (80-) 2016, 353:300–305. [DOI] [PMC free article] [PubMed] [Google Scholar]; ** In this seminal study, the authors discover that Chd4 drives the deposition of the histone variant H2A.z at promoters of activity genes, leading to their shutoff and consequent dendrite elimination and sparse sensorimotor encoding in granule neurons of the cerebellar cortex.
  • 45.Buschbeck M, Hake SB: Variants of core histones and their roles in cell fate decisions, development and cancer. Nat Rev Mol Cell Biol 2017, 18:299–314. [DOI] [PubMed] [Google Scholar]
  • 46.Kovač K, Sauer A, Mačinković I, Awe S, Finkernagel F, Hoffmeister H, Fuchs A, Müller R, Rathke C, Längst G, et al. : Tumour-associated missense mutations in the dMi-2 ATPase alters nucleosome remodelling properties in a mutation-specific manner. Nat Commun 2018, 9:2112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Willemsen MH, Nijhof B, Fenckova M, Nillesen WM, Bongers EMHF, Castells-Nobau A, Asztalos L, Viragh E, van Bon BWM, Tezel E, et al. : GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila. J Med Genet 2013, 50:507–514. [DOI] [PubMed] [Google Scholar]
  • 48.de Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, et al. : Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability. N Engl J Med 2012, 367:1921–1929. [DOI] [PubMed] [Google Scholar]
  • 49.Cukier HN, Rabionet R, Konidari I, Rayner-Evans MY, Baltos ML, Wright HH, Abramson RK, Martin ER, Cuccaro ML, Pericak-Vance MA, et al. : Novel variants identified in methyl-CpG-binding domain genes in autistic individuals. Neurogenetics 2010, 11:291–303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Helsmoortel C, Vulto-Van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, Van Den Ende J, Schuurs-Hoeijmakers JHM, Marcelis CL, Willemsen MH, Vissers LELM, et al. : A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet 2014, 46:380–384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Ostapcuk V, Mohn F, Carl SH, Basters A, Hess D, lesmantavicius V, Lampersberger L, Flemr M, Pandey A, Thomä NH, et al. : Activity-dependent neuroprotective protein recruits HP1 and CHD4 to control lineage-specifying genes. Nature 2018, doi: 10.1038/s41586-018-0153-8. [DOI] [PubMed] [Google Scholar]
  • 52.Bergman JEH, Janssen N, Hoefsloot LH, Jongmans MCJ, Hofstra RMW, van Ravenswaaij-Arts CMA: CHD7 mutations and CHARGE syndrome: The clinical implications of an expanding phenotype. J Med Genet 2011, 48:334–342. [DOI] [PubMed] [Google Scholar]
  • 53.Feng W, Kawauchi D, Körkel-Qu H, Deng H, Serger E, Sieber L, Ariel Lieberman J, Jimeno-Gonzalez S, Lambo S, Hanna BS, et al. : Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme. Nat Commun 2017, 8. [DOI] [PMC free article] [PubMed] [Google Scholar]; * This article shows that Chd7 coordinates TopIIb function to orchestrate terminal differentiation in cerebellar granule neurons, suggesting a functional link between chromatin remodeling and DNA gyrase activity in neurons.
  • 54.Hurd EA, Poucher HK, Cheng K, Raphael Y, Martin DM: The ATP-dependent chromatin remodeling enzyme CHD7 regulates pro-neural gene expression and neurogenesis in the inner ear. Development 2010, 137:3139–3150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Feng W, Khan MA, Bellvis P, Zhu Z, Bernhardt O, Herold-Mende C, Liu HK: The chromatin remodeler CHD7 regulates adult neurogenesis via activation of soxc transcription factors. Cell Stem Cell 2013, 13:62–72. [DOI] [PubMed] [Google Scholar]
  • 56.Schnetz MP, Bartels CF, Shastri K, Balasubramanian D, Zentner GE, Balaji R, Zhang X, Song L, Wang Z, LaFramboise T, et al. : Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res 2009, 19:590–601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Bajpai R, Chen DA, Rada-lglesias A, Zhang J, Xiong Y, Helms J, Chang CP, Zhao Y, SwigutT, Wysocka J: CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature 2010, 463:958–962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.King IF, Yandava CN, Mabb AM, Hsiao JS, Huang HS, Pearson BL, Calabrese JM, Starmer J, Parker JS, Magnuson T, et al. : Topoisomerases facilitate transcription of long genes linked to autism. Nature 2013, 501:58–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Suetterlin P, Hurley S, Mohan C, Riegman KLH, Pagani M, Caruso A, Ellegood J, Galbusera A, Crespo-Enriquez I, Michetti C, et al. : Altered neocortical gene expression, brain overgrowth and functional over-connectivity in chd8 haploinsufficient mice. Cereb Cortex 2018, 28:2192–2206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Jung H, Park H, Choi Y, Kang H, Lee E, Kweon H, Roh JD, Ellegood J, Choi W, Kang J, et al. : Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice. Nat Neurosci 2018, 21:1218–1228. [DOI] [PubMed] [Google Scholar]; ** In this paper, the authors identify behavioral phenotypes in heterozygous Chd8 null male mice that do not appear in their female counterparts. The sexually dimorphic behavioral phenotypes are linked to electrophysiologic and transcriptomic alterations that are different between male and female heterozygous Chd8 null mice, suggesting a neuroprotective effect within female mice that might prevent behavioral abnormalities when carrying a single Chd8 null allele.
  • 61.Gompers AL, Su-Feher L, Ellegood J, Copping NA, Riyadh MA, Stradleigh TW, Pride MC, Schaffler MD, Wade AA, Catta-Preta R, et al. : Germline Chd8 haploinsufficiency alters brain development in mouse. Nat Neurosci 2017, 20:1062–1073. [DOI] [PMC free article] [PubMed] [Google Scholar]; * In a detailed analysis of the neuroanatomical and transcriptomic alterations in the brain of heterozygous Chd8 null mouse, the authors demonstrate increases in the size of brain structures, which is also apparent in patients with autism spectrum disorder carrying deleterious Chd8 mutations. Increased brain size is coupled to increased proliferation in these mice.
  • 62.Platt RJ, Zhou Y, Slaymaker IM, Shetty AS, Weisbach NR, Kim JA, Sharma J, Desai M, Sood S, Kempton HR, et al. : Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep 2017, 19:335–350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Durak O, Gao F, Kaeser-Woo YJ, Rueda R, Martorell AJ, Nott A, Liu CY, Watson LA, Tsai LH: Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. Nat Neurosci 2016, 19:1477–1488. [DOI] [PMC free article] [PubMed] [Google Scholar]; * This article shows that Chd8 knockdown in cortical neuron precursors leads to reduced proliferation and increased differentiation of these cells, thereby causing behavioral deficits. Wnt signaling, which is induced by Chd8 in cells, can rescue the phenotypes observed in mice with Chd8 knockdown in cortical neuron precursors, suggesting a mechanistic link between Chd8 and Wnt signaling in the regulation of cortical neuron differentiation.
  • 64.Katayama Y, Nishiyama M, Shoji H, Ohkawa Y, Kawamura A, Sato T, Suyama M, Takumi T, Miyakawa T, Nakayama Kl: CHD8 haploinsufficiency results in autistic-like phenotypes in mice. Nature 2016, 537:675–679. [DOI] [PubMed] [Google Scholar]; ** In this paper, the authors establish for the first time a role for Chd8 in brain development. Knockout of one allele of Chd8 leads to abnormal behaviors in mice. Chd8 binds to promoters of genes in the brain to regulate a large autism-spectrum disorder-associated gene network.
  • 65.Zhao C, Dong C, Frah M, Deng Y, Marie C, Zhang F, Xu L, Ma Z, Dong X, Lin Y, et al. : Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair. Dev Cell 2018, 45:753–768. e8. [DOI] [PMC free article] [PubMed] [Google Scholar]; *** In this study, the authors uncover a mechanism underlying Chd8-dependent oligodendrocyte precursor proliferation. Chd8 interacts with MLL complex members, which catalyze H3K4 trimethylation, to increase chromatin accessibility and H3K4me3 at gene promoters.
  • 66.Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, et al. : CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc Natl Acad Sci 2014, 111: E4468–E4477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.de Dieuleveult M, Yen K, Hmitou I, Depaux A, Boussouar F, Dargham DB, Jounier S, Humbertclaude H, Ribierre F, Baulard C, et al. : Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells. Nature 2016, 530:113–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Wang P, Mokhtari R, Pedrosa E, Kirschenbaum M, Bayrak C, Zheng D, Lachman HM: CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells. Mol Autism 2017, 8:1–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, et al. : The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun 2015, 6:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.He D, Marie C, Zhao C, Kim B, Wang J, Deng Y, Clavairoly A, Frah M, Wang H, He X, et al. : Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination. Nat Neurosci 2016, 19:678–689. [DOI] [PMC free article] [PubMed] [Google Scholar]; * This article demonstrates that Chd7 and Sox10 control oligodendrocyte differentiation by regulating similar genomic sites. Additionally, CHARGE syndrome patients have reduced cerebral white matter volume.
  • 71.Marie C, Clavairoly A, Frah M, Hmidan H, Yan J, Zhao C, Van Steenwinckel J, Daveau R, Zalc B, Hassan B, et al. : Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8. Proc Natl Acad Sci 2018, 115:201802620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Quan J, Yusufzai T: The tumor suppressor chromodomain helicase DNA-binding protein 5 (CHD5) remodels nucleosomes by unwrapping. J Biol Chem 2014, 289:20717–20726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Whyte WA, Bilodeau S, Orlando DA, Hoke HA, Frampton GM, Foster CT, Cowley SM, Young RA: Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 2012, 482:221–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L, et al. : LSD1 Is a Subunit of the NuRD Complex and Targets the Metastasis Programs in Breast Cancer. Cell 2009, 138:660–672. [DOI] [PubMed] [Google Scholar]
  • 75.Ruhl DD, Jin J, Cai Y, Swanson S, Florens L, Washburn MP, Conaway RC, Conaway JW, Chrivia JC: Purification of a human SRCAP complex that remodels chromatin by incorporating the histone variant H2A.Z into nucleosomes. Biochemistry 2006, 45:5671–5677. [DOI] [PubMed] [Google Scholar]
  • 76.Pradhan SK, Su T, Yen L, Jacquet K, Huang C, Côté J, Kurdistani SK, Carey MF: EP400 Deposits H3.3 into Promoters and Enhancers during Gene Activation. Mol Cell 2016, 61:27–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Yen K, Vinayachandran V, Pugh BF: XSWR-C and INO80 chromatin remodelers recognize nucleosome-free regions near +1 nucleosomes. Ce// 2013, 154:1246–1256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Stefanelli G, Azam AB, Walters BJ, Brimble MA, Gettens CP, Bouchard-Cannon P, Cheng H-YM, Davidoff AM, Narkaj K, Day JJ, et al. : Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus. Cell Rep 2018, 22:1124–1131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Zovkic IB, Paulukaitis BS, Day JJ, Etikala DM, Sweatt JD: Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 2014, 515:582–586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Teves SS, Henikoff S: Transcription-generated torsional stress destabilizes nucleosomes. Nat Struct Mol Biol 2014, 21:88–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Havas K, Flaus A, Phelan M, Kingston R, Wade PA, Lilley DMJ, Owen-Hughes T, others: Generation of Superhelical Torsion by ATP-Dependent Chromatin Remodeling Activities* SWI/SNF Chromatin Remodeling Requires Changes in DNA Topology.Cell 2000, 103:1133. [DOI] [PubMed] [Google Scholar]
  • 82.Lia G, Praly E, Ferreira H, Stockdale C, Tse-Dinh YC, Dunlap D, Croquette V, Bensimon D, Owen-Hughes T: Direct observation of DNA distortion by the RSC complex. Mol Cell 2006, 21:417–425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E, Halder R, Burkhardt S, Stewart AF, Fischer A: Histone-Methyltransferase MLL2 (KMT2B) Is Required for Memory Formation in Mice. J Neurosci 2013, 33:3452–3464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Kerimoglu C, Sakib MS, Jain G, Benito E, Burkhardt S, Capece V, Kaurani L, Halder R, Agís-Balboa RC, Stilling R, et al. : KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions. Cell Rep 2017, 20:538–548. [DOI] [PubMed] [Google Scholar]

RESOURCES