CTCF Interacts with and Recruits the Largest Subunit of RNA Polymerase II to CTCF Target Sites Genome-Wide

Chernukhin, Igor; Shamsuddin, Shaharum; Kang, Sung Yun; Bergström, Rosita; Kwon, Yoo-Wook; Yu, Wenqiang; Whitehead, Joanne; Mukhopadhyay, Rituparna; Docquier, France; Farrar, Dawn; Morrison, Ian; Vigneron, Marc; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Loukinov, Dmitri; Lobanenkov, Victor; Ohlsson, Rolf; Klenova, Elena

doi:10.1128/mcb.01993-06

Cited by 154 publications

(140 citation statements)

References 64 publications

(77 reference statements)

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“…In addition, CTCF was shown to interact directly with RNAPII (28). CTCF was shown to block enhancerand promoter-looping interactions (19,20) or to mark the boundary between active and inactive chromatin regions to establish chromatin domains and to insulate neighboring promoters from interfering with each other (29,30).…”

Section: Discussionmentioning

confidence: 99%

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

Guo

Monahan

et al. 2012

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

242

329

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The closely linked human protocadherin (Pcdh) α, β, and γ gene clusters encode 53 distinct protein isoforms, which are expressed in a combinatorial manner to generate enormous diversity on the surface of individual neurons. This diversity is a consequence of stochastic promoter choice and alternative pre-mRNA processing. Here, we show that Pcdhα promoter choice is achieved by DNA looping between two downstream transcriptional enhancers and individual promoters driving the expression of alternate Pcdhα isoforms. In addition, we show that this DNA looping requires specific binding of the CTCF/cohesin complex to two symmetrically aligned binding sites in both the transcriptionally active promoters and in one of the enhancers. These findings have important implications regarding enhancer/promoter interactions in the generation of complex Pcdh cell surface codes for the establishment of neuronal identity and self-avoidance in individual neurons.T he clustered protocadherin (Pcdh) genes are expressed in the nervous system and organized into three closely linked clusters (α, β, and γ) (1-5). The human Pcdhα gene cluster contains 13 highly similar variable first exons (α1 to α13) arrayed in tandem and two more distantly related c-type variable first exons designated αc1 and αc2 (Fig. 1A). The variable first exons encode the extracellular, transmembrane, and juxtamembrane intracellular domains of the Pcdhα proteins. Each of these 15 variable first exons is cis-spliced to a single set of three downstream constant exons that encode a distal intracellular domain (1-3). The human β cluster is located downstream from the α cluster and contains a tandem array of 16 highly similar variable exons but with no constant exons, whereas the γ cluster contains 22 variable first exons arrayed in tandem and divided into three types (γa1 to γa12, γb1 to γb7, and γc3 to γc5) (Fig. 1D). As in the case of the α cluster, each of these 22 γ variable first exons is cis-spliced to a single set of three downstream constant exons, which are distinct from the α constant exons, to generate diverse γ mRNAs (1, 3, 6). Analyses of the α and γ transcripts have revealed that highly similar Pcdh alternate isoforms are expressed in a stochastic fashion, whereas all of the c-type divergent isoforms, αc1 and αc2 in the α cluster and γc3, γc4, and γc5 in the γ cluster, are expressed ubiquitously in all cells (1-3, 5, 7). Hereafter, we refer to the c-type genes as "ubiquitously expressed" in contrast to the "alternately expressed" Pcdh genes ( Fig. 1 A and D). A combination of stochastic activation of alternate promoters and constitutive activation of c-type ubiquitous promoters generates enormous single-cell diversity on the surface of individual neurons.Significant advances have been made in understanding the mechanisms by which individual neurons express distinct combinations of the clustered Pcdh genes (2, 3, 8-10). Two long-range cis-regulatory elements in the α cluster, HS5-1 and HS7 (hypersensitive sites 5-1 and 7), function as developmental and tissue...

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Section: Discussionmentioning

confidence: 99%

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

Guo

Monahan

et al. 2012

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

242

329

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“…This initial generalized deregulation of gene transcription (animation) does not require de novo viral protein synthesis. How latent virus DNA quickly undergoes generalized transcriptional deregulation resulting in transcription of multiple immediate-early, early and late genes without prior protein or virus DNA synthesis is unknown, but may involve RNA polymerase II recruitment at CTCF/cohesin complexes (Chernukhin et al, 2007;Wada et al, 2009;Taslim et al, 2012). Interestingly, CTCF-directed cohesin rings can tether DNA strands present on different chromosomes for coordinated transcription (Kagey et al, 2010).…”

Section: Alphaherpesvirus Gene Transcription Is Deregulated During VImentioning

confidence: 99%

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

137

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Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. Received 5 January 2015Accepted 18 March 2015 IntroductionHerpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses usually acquired early in life. Primary HSV-1 infection is usually localized and may be asymptomatic, although it can produce a more widespread systemic infection in neonates and immunocompromised adults, whilst primary VZV infection is systemic and results in childhood varicella (chickenpox). During primary infection, both viruses gain access to neurons most likely through retrograde transport from the site of cutaneous lesion...

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“…3 Ctcf regulates chromatin architecture together with cohesion proteins, which are enriched at Ctcf-binding sites. [5][6][7] In addition, multiple functions of Ctcf are enabled by interaction with different binding partners like transcription factors (Yy1, Kaiso and YB-1), [8][9][10] chromatin modifying proteins (Sin3a, CHD8, Suz12), [11][12][13] RNA polymerase II 14 and poly(ADP-ribose) polymerase-1. 15 Recently, Ctcf was found to control MHC class II gene expression, 16 and it was reported that enforced overexpression of Ctcf in DC caused increased apoptosis, reduced proliferation and impaired differentiation.…”

Section: Introductionmentioning

confidence: 99%

The DNA-binding factor Ctcf critically controls gene expression in macrophages

et al. 2013

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CTCF Interacts with and Recruits the Largest Subunit of RNA Polymerase II to CTCF Target Sites Genome-Wide

Cited by 154 publications

References 64 publications

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

The DNA-binding factor Ctcf critically controls gene expression in macrophages

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