A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain

Balan, Shabeesh; Iwayama, Yoshimi; Ohnishi, Tetsuo; Fukuda, Mikiko; Shirai, Akira; Yamada, Ayumi; Weirich, Sara; Schuhmacher, Maren Kirstin; Dileep, Kalarickal V.; Endō, Toyoshige; Hisano, Yu; Kotoshiba, Kaoru; Toyota, Tomoko; Otowa, Takeshi; Kuwabara, Hitoshi; Tochigi, Mamoru; Watanabe, Akïharu; Ohba, Hideki; Maekawa, Motoko; Toyoshima, Manabu; Sasaki, Tsukasa; Nakamura, Kazuhiko; Tsujii, Masatsugu; Matsuzaki, Hideo; Zhang, Kam Y. J.; Jeltsch, Albert; Shinkai, Yoichi; Yoshikawa, Takeo

doi:10.1038/s41380-021-01199-7

Cited by 17 publications

(10 citation statements)

References 72 publications

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“…Sociability tests revealed that Zfp661 -/mice displayed deficits in social interactions (Fig. 5D), similar to mice that have reduced Pcdh diversity (42,43).…”

Section: Loss Of Zfp661 Causes Deficits In Dendritic Arborization And...mentioning

confidence: 66%

“…Both the loss of Zfp661 (Figs. 5A to 5D) and reduced Pcdh diversity from direct genetic ablation (39)(40)(41)(42)(43) can induce cortical dendritic arborization defects and social deficits. Autism Spectrum Disorder (ASD) is one of most common brain developmental disorders in humans associated with social deficits, which impacts about 2.3% children in the United States (45).…”

Section: Discussionmentioning

confidence: 99%

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CTCF barrier breaking by ZFP661 promotes protocadherin diversity in mammalian brains

Jin

Ralls

et al. 2023

Preprint

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Mammalian brains are larger and more densely packed with neurons than reptiles, but the genetic mechanisms underlying the increased connection complexity amongst neurons are unclear. The expression diversity of clustered protocadherins (Pcdhs), which is controlled by CTCF and cohesin, is crucial for proper dendritic arborization and cortical connectivity in vertebrates. Here, we identify a highly-conserved and mammalian-restricted protein, ZFP661, that binds antagonistically at CTCF barriers at the Pcdh locus, preventing CTCF from trapping cohesin. ZFP661 balances the usage of Pcdh isoforms and increases Pcdh expression diversity. Loss ofZfp661causes cortical dendritic arborization defects and autism-like social deficits in mice. Our study reveals both a novel mechanism that regulates the trapping of cohesin by CTCF and a mammalian adaptation that promoted Pcdh expression diversity to accompany the expanded mammalian brain.

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“…Sociability tests revealed that Zfp661 -/mice displayed deficits in social interactions (Fig. 5D), similar to mice that have reduced Pcdh diversity (42,43).…”

Section: Loss Of Zfp661 Causes Deficits In Dendritic Arborization And...mentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

CTCF barrier breaking by ZFP661 promotes protocadherin diversity in mammalian brains

Jin

Ralls

et al. 2023

Preprint

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“…Furthermore, multiple histone H3 methyltransferases normally play redundant roles in the methylation of specific lysine residues 10 . Therefore, conditional mutations of individual methyltransferases do not usually result in a complete loss of histone H3 methylation 12,[37][38][39] . To overcome these limitations, we have optimized the overexpression and temporal control of histone H3 K-to-M mutants to inhibit the endogenous methylation of histone H3 in early postnatal and adult cortical neurons.…”

Section: Discussionmentioning

confidence: 99%

A Vector System Encoding Histone H3 Mutants Facilitates Manipulations of the Neuronal Epigenome

Warren,

Xiong,

Robles

et al. 2024

Preprint

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The differentiation of developmental cell lineages is associated with genome-wide modifications in histone H3 methylation. However, the causal role of histone H3 methylation in transcriptional regulation and cell differentiation has been difficult to test in mammals. The experimental overexpression of histone H3 mutants carrying lysine-to-methionine (K-to-M) substitutions has emerged as an alternative tool for inhibiting the endogenous levels of histone H3 methylation at specific lysine residues. Here, we leverage the use of histone K-to-M mutants by creating Enhanced Episomal Vectors that enable the simultaneous depletion of multiple levels of histone H3 lysine 4 (H3K4) or lysine 9 (H3K9) methylation in projection neurons of the mouse cerebral cortex. Our approach also facilitates the simultaneous depletion of H3K9 and H3K27 trimethylation (H3K9me3 and H3K27me3, respectively) in cortical neurons. In addition, we report a tamoxifen-inducible Cre-FLEX system that allows the activation of mutant histones at specific developmental time points or in the adult cortex, leading to the depletion of specific histone marks. The tools presented here can be implemented in other experimental systems, such as human in vitro models, to test the combinatorial role of histone methylations in developmental fate decisions and the maintenance of cell identity.

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“…Typically, AT-biased sequence is packaged as heterochromatin and silenced. Work on olfactory receptors, clustered protocadherins, and secreted liver proteins suggest that these gene families are expressed from the context of constitutive heterochromatin, which appears to be present prior to expression and to be retained on family members that are not expressed (Balan et al, 2021; Magklara et al, 2011; Nicetto et al, 2019; Toyoda et al, 2014; Williams et al, 2021). CpG islands also function as molecular beacons: they mark transcription start sites, serve as recombination hotspots in the absence of PRDM9, and act as replication origins in meiosis (Antequera and Bird, 1999; Baker et al, 2017; Pratto et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Emergence and influence of sequence bias in evolutionarily malleable, mammalian tandem arrays

Brovkina

Chapman

Holding³

et al. 2022

Preprint

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The radiation of mammals at the extinction of the dinosaurs produced a plethora of new forms--as diverse as bats, dolphins, and elephants--in only 10-20 million years. Behind the scenes, adaptation to new niches is accompanied by extensive innovation in large families of genes that allow animals to contact the environment, including chemosensors, xenobiotic enzymes, and immune and barrier proteins. These large gene families share a common genomic organization and are often characterized by unusual modes of transcriptional regulation: they are clustered in tandem arrays in AT-biased isochores and exhibit tissue-specific and sometimes stochastic expression. Here, we use population genetic data and evolutionary analysis to examine the relationship between gene family diversification and genomic organization in mammals. First, we find that AT bias emerges as gene families expand in cis. Second, AT-biased, clustered gene families experience relatively low rates of de novo point mutation, and we suggest that multi-copy gene families have accrued high AT content due to relaxed selection compared to single-copy genes. Finally, we find that AT-biased, clustered gene families exhibit low rates of recombination and are depleted for binding of the recombination-seeding factor PRDM9. We posit that tolerance of point mutation and intolerance of recombination together result in depressed GC content of multi-copy versus single-copy genes. In turn, differential sequence content of gene blooms exerts a profound effect on their chromatin organization and transcriptional regulation.

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A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain

Cited by 17 publications

References 72 publications

CTCF barrier breaking by ZFP661 promotes protocadherin diversity in mammalian brains

CTCF barrier breaking by ZFP661 promotes protocadherin diversity in mammalian brains

A Vector System Encoding Histone H3 Mutants Facilitates Manipulations of the Neuronal Epigenome

Emergence and influence of sequence bias in evolutionarily malleable, mammalian tandem arrays

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