Controlling Long-Range Genomic Interactions at a Native Locus by Targeted Tethering of a Looping Factor

Deng, Wulan; Lee, Jongjoo; Wang, Hongxin; Miller, Jeff F.; Reik, Andreas; Gregory, Philip D.; Dean, Ann; Blobel, Gerd A.

doi:10.1016/j.cell.2012.03.051

Cited by 671 publications

(617 citation statements)

References 49 publications

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“…Because LDB1 also has been reported to interact with other transcription factors, it is tempting to suggest a potentially general role for LDB1 in regulating cell typespecific, enhancer-dependent gene-expression programs. LDB1-mediated promoter:enhancer looping has been reported in the β-globin locus based on the homodimerization of LDB1 occupying both enhancer and promoter sites (22)(23)(24). Our data show that, in corticotropes, LDB1 can mediate looping to promoters without detectable promoter LDB1 binding.…”

Section: Discussionmentioning

confidence: 61%

“…LDB1 was postulated to play an important role in promoter:enhancer looping events and as a coactivator in several systems (21)(22)(23)(24)(33)(34)(35). To investigate its roles in gene transcription and in promoter:enhancer looping events in the POMC lineage, we performed GRO-seq after Ldb1 knockdown and observed that, of 3,378 genes down-regulated by siLdb1, 927 transcription units are located in direct proximity to the LDB1-occupied enhancers.…”

Section: Ldb1mentioning

confidence: 99%

“…Lim domain-binding (LDB)/nuclear LIM interactor (NLI)/ cofactor of LIM homeodomain protein (CLIM), the mammalian homolog of CHIP, has been demonstrated to be a critical factor for multiple developmental systems and to be a component of LIM homeodomain codes that determine neuronal subtype specification in the spinal cord (3,20,21). Recently, using an engineered transcription unit as a model, LIM domain-binding protein 1 (LDB1) has been reported to be capable of mediating promoter:enhancer looping through LDB1 homodimerization (22)(23)(24).…”

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confidence: 99%

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Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program

Zhang

Tanasă

Merkurjev

et al. 2015

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

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Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of LIM domain-binding protein 1 (LDB1)/cofactor of LIM homeodomain protein 2/nuclear LIM interactor, interacting with the enhancer-binding protein achaete-scute complex homolog 1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target genes. Although LDB1-dependent activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of metastasis-associated 1 family, member 2, a component of the nucleosome remodeling deacetylase complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type.

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Section: Discussionmentioning

confidence: 61%

Section: Ldb1mentioning

confidence: 99%

mentioning

confidence: 99%

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Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program

Zhang

Tanasă

Merkurjev

et al. 2015

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

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“…These findings suggest that risk-associated SNPs might abrogate chromatin looping and thus result in reduced promoter activity and subsequent transcription. 33 In addition, the risk SNPs reduced PRE1 activity on the CUPID1 promoter. However, in the absence of chromatin looping between PRE1 and the CUPID1 and CUPID2 promoter, the significance of this observation is unclear.…”

Section: Discussionmentioning

confidence: 98%

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Betts

Marjaneh

Al-Ejeh

et al. 2017

The American Journal of Human Genetics

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Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

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“…In addition to binding sites containing GATA-E-box composite elements, like the +9.5 site, TAL1 occupies GATA motif-containing sites lacking a consensus E-box, presumably via recruitment by the GATA factor (28). The LIM domain binding-1 coregulator LDB1 promotes chromatin looping (39,40) and facilitates HSC maintenance, primitive hematopoietic progenitor generation, and erythroid differentiation (37,(41)(42)(43)(44). Certain patients with MonoMAC who lack GATA2 coding region mutations harbored deletion or point mutations in Fig.…”

Section: Significancementioning

confidence: 99%

Mechanism governing a stem cell-generating cis -regulatory element

Sanalkumar

Johnson

Gào

et al. 2014

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

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The unremitting demand to replenish differentiated cells in tissues requires efficient mechanisms to generate and regulate stem and progenitor cells. Although master regulatory transcription factors, including GATA binding protein-2 (GATA-2), have crucial roles in these mechanisms, how such factors are controlled in developmentally dynamic systems is poorly understood. Previously, we described five dispersed Gata2 locus sequences, termed the −77, −3.9, −2.8, −1.8, and +9.5 GATA switch sites, which contain evolutionarily conserved GATA motifs occupied by GATA-2 and GATA-1 in hematopoietic precursors and erythroid cells, respectively. Despite common attributes of transcriptional enhancers, targeted deletions of the −2.8, −1.8, and +9.5 sites revealed distinct and unpredictable contributions to Gata2 expression and hematopoiesis. Herein, we describe the targeted deletion of the −3.9 site and mechanistically compare the −3.9 site with other GATA switch sites. The −3.9 −/− mice were viable and exhibited normal Gata2 expression and steady-state hematopoiesis in the embryo and adult. We established a Gata2 repression/reactivation assay, which revealed unique +9.5 site activity to mediate GATA factor-dependent chromatin structural transitions. Loss-of-function analyses provided evidence for a mechanism in which a mediator of long-range transcriptional control [LIM domain binding 1 (LDB1)] and a chromatin remodeler [Brahma related gene 1 (BRG1)] synergize through the +9.5 site, conferring expression of GATA-2, which is known to promote the genesis and survival of hematopoietic stem cells.cis element | HSCs W hereas proximal promoter sequences assemble the basal transcriptional machinery and RNA polymerase, distant cis-regulatory elements often confer tissue-specific or contextdependent transcriptional regulation. Enhancer elements reside many kilobases upstream or downstream of a promoter or within introns, and extensive efforts have focused on elucidating "action-at-a-distance" mechanisms (1). Long-range transcriptional control involves physical interactions between proteins bound at distal regions and promoter sequences and higher order structural transitions, including subnuclear relocalization of target loci (2-4). Given the high frequency of long-range mechanisms at mammalian loci and the mutations that disrupt the function of such elements in pathological conditions, elucidating the underlying mechanisms in development,

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Controlling Long-Range Genomic Interactions at a Native Locus by Targeted Tethering of a Looping Factor

Cited by 671 publications

References 49 publications

Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program

Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Mechanism governing a stem cell-generating cis -regulatory element

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