CTCF Is Required for Neural Development and Stochastic Expression of Clustered Pcdh Genes in Neurons

Hirayama, Teruyoshi; Tarusawa, Etsuko; Yoshimura, Yumiko; Galjart, Niels; Yagi, Takeshi

doi:10.1016/j.celrep.2012.06.014

Cited by 169 publications

(187 citation statements)

References 63 publications

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“…Upon knockdown of Ctcf, there was noticeably reduced expression of a number of the Pcdh genes, compared with the negative control (Fig. 4A), similar to the down-regulation of clustered Pcdh genes observed in Ctcf-deficient mouse brains (39) (Fig. 4A).…”

Section: Smchd1 and Ctcf Mediate Opposite Effects On The Expression Osupporting

confidence: 69%

Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation

Chen

Moore

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

143

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Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1-chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.Smchd1 | epigenetic control | clustered protocadherins | Ctcf

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Section: Smchd1 and Ctcf Mediate Opposite Effects On The Expression Osupporting

confidence: 69%

Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation

Chen

Moore

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

143

View full text Add to dashboard Cite

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“…In particular, the clustered Pcdh genes are organized into variable and constant regions and generate enormous neural diversity by stochastic promoter choice combined with alternative pre-mRNA splicing (51)(52)(53). Recently, the neural expression of the clustered Pcdh genes was found to be controlled by both CTCF and NRSF (30,38,54,55). In particular, the CTCF/ cohesin complex plays a pivotal role in the promoter choice of the clustered Pcdh genes by mediating specific DNA looping interactions between enhancers and selective variable promoters (30).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Protocadherin Celsr3 Gene and Its Role in Globus Pallidus Development and Connectivity

Jia

Guo

Tang

et al. 2014

Molecular and Cellular Biology

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The globus pallidus (GP) is a central component of basal ganglia whose malfunctions cause a variety of neuropsychiatric disorders as well as cognitive impairments in neurodegenerative diseases such as Parkinson's disease. Here we report that the protocadherin gene Celsr3 is regulated by the insulator CCCTC-binding factor (CTCF) and the repressor neuron-restrictive silencer factor (NRSF, also known as REST) and is required for the development and connectivity of GP. Specifically, CTCF/cohesin and NRSF inhibit the expression of Celsr3 through specific binding to its promoter. In addition, we found that the Celsr3 promoter interacts with CTCF/cohesin-occupied neighboring promoters. In Celsr3 knockout mice, we found that the ventral GP is occupied by aberrant calbindin-positive cholinergic neurons ectopic from the nucleus basalis of Meynert. Furthermore, the guidepost cells for thalamocortical axonal development are missing in the caudal GP. Finally, axonal connections of GP with striatum, subthalamic nucleus, substantia nigra, and raphe are compromised. These data reveal the essential role of Celsr3 in GP development in the basal forebrain and shed light on the mechanisms of the axonal defects caused by the Celsr3 deletion. The genes Celsr1, Celsr2, and Celsr3 are members of the mammalian nonclustered protocadherin (Pcdh) family that are homologous to the fly flamingo gene (1). The flamingo gene plays important roles in dendrite development and self-avoidance, axonal projection, and planar cell polarity (PCP) in Drosophila (2-7). The mammalian Celsr genes are the so-called core PCP genes that have conserved as well as newly diversified functions. In particular, the vertebrate Celsr3 gene has been shown to regulate axonal projections, dendrite development, neuronal migration, ciliogenesis, and retina circuit development (8-16). However, very little is known about Celsr gene regulation.The globus pallidus (GP) is a central nucleus of the basal ganglia (BG) (17,18). Malfunctions of GP lead to several neuropathological conditions, such as Parkinson's disease, as well as many neuropsychiatric diseases (19). The mouse GP, which corresponds to the GPe in primates, contains approximately 44% of parvalbumin-positive (PV ϩ ) neurons and 1% of calretinin-positive (CR ϩ ) interneurons, but calbindin-positive (CB ϩ ) cells are rare (20,21). The GP is traditionally thought to be derived from the medial ganglionic eminence (MGE) (22); however, recent studies have revealed that, in addition to MGE, subpopulations of GP cells are also generated from the lateral ganglionic eminence (LGE) and preoptic area (POA) (21, 23). The molecular requirements for GP development are not known, but specific transcription factors appear to be essential. For example, Nkx2-1 is required for the generation of most GP neurons except the Npas1 ϩ type from LGE (23). In addition, Lhx6/8 double-mutant mice do not have a well-defined GP (24).The GP functions through extensive axonal connections with other brain nuclei. For example, GP receives GABAergic ax...

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“…To test the targeting of predicted transcription factors at these distal sites, we chose two factors for each stage for which genome-wide binding data sets were publicly available for matching stages of neuronal differentiation (SOX2 and SOX3 for NP; LHX3 and ISL1 for TND1; and CTCF and RFX1 for TND10) and were shown to be critical for the respective stages ( Fig. 3D-F; Uwanogho et al 1995;Sharma et al 1998;Tanaka et al 2011;Dekker 2012;Hirayama et al 2012;Lee et al 2012Lee et al , 2013. Comparative analysis of these ChIP-seq data sets with open and H3K27ac-positive sites revealed a high enrichment for these factors at distal regions in the respective stages (Fig.…”

Section: Distal Regulatory Elements Recruit Distinct Transcription Famentioning

confidence: 99%

Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity

et al. 2015

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Gene regulation in mammals involves a complex interplay between promoters and distal regulatory elements that function in concert to drive precise spatiotemporal gene expression programs. However, the dynamics of the distal gene regulatory landscape and its function in the transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here, we performed a combinatorial analysis of genome-wide data sets for chromatin accessibility (FAIREseq) and the enhancer mark H3K27ac, revealing the highly dynamic nature of distal gene regulation during neurogenesis, which gets progressively restricted to distinct genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further find that the distal accessible and active regions serve as target sites for distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. Mature neurons respond to a sustained activity of NMDA receptors by epigenetic reprogramming at a large number of distal regulatory regions as well as dramatic reorganization of super-enhancers. Such massive remodeling of the distal regulatory landscape in turn results in a transcriptome that confers a transient loss of neuronal identity and gain of cellular plasticity. Furthermore, NMDA receptor activity also induces many novel prosurvival genes that function in neuroprotective pathways. Taken together, these findings reveal the dynamics of the distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate the transcriptome underlying neuronal development and activity.

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CTCF Is Required for Neural Development and Stochastic Expression of Clustered Pcdh Genes in Neurons

Cited by 169 publications

References 63 publications

Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation

Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation

Regulation of the Protocadherin Celsr3 Gene and Its Role in Globus Pallidus Development and Connectivity

Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity

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