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      Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus

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          Abstract

          The human 8q24 gene desert contains multiple enhancers that form tissue-specific long-range chromatin loops with the MYC oncogene, but how chromatin looping at the MYC locus is regulated remains poorly understood. Here we demonstrate that a long noncoding RNA (lncRNA), CCAT1-L, is transcribed specifically in human colorectal cancers from a locus 515 kb upstream of MYC. This lncRNA plays a role in MYC transcriptional regulation and promotes long-range chromatin looping. Importantly, the CCAT1-L locus is located within a strong super-enhancer and is spatially close to MYC. Knockdown of CCAT1-L reduced long-range interactions between the MYC promoter and its enhancers. In addition, CCAT1-L interacts with CTCF and modulates chromatin conformation at these loop regions. These results reveal an important role of a previously unannotated lncRNA in gene regulation at the MYC locus.

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          Long noncoding RNA as modular scaffold of histone modification complexes.

          Miao-Chih Tsai, Ohad Manor, Yue Wan … (2010)
          Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
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            Identification of c-MYC as a target of the APC pathway.

            T He, A. B. Sparks, C Rago … (1998)
            The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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              Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting

              Tomas Cermak, Erin L. Doyle, Michelle Christian … (2011)
              TALENs are important new tools for genome engineering. Fusions of transcription activator-like (TAL) effectors of plant pathogenic Xanthomonas spp. to the FokI nuclease, TALENs bind and cleave DNA in pairs. Binding specificity is determined by customizable arrays of polymorphic amino acid repeats in the TAL effectors. We present a method and reagents for efficiently assembling TALEN constructs with custom repeat arrays. We also describe design guidelines based on naturally occurring TAL effectors and their binding sites. Using software that applies these guidelines, in nine genes from plants, animals and protists, we found candidate cleavage sites on average every 35 bp. Each of 15 sites selected from this set was cleaved in a yeast-based assay with TALEN pairs constructed with our reagents. We used two of the TALEN pairs to mutate HPRT1 in human cells and ADH1 in Arabidopsis thaliana protoplasts. Our reagents include a plasmid construct for making custom TAL effectors and one for TAL effector fusions to additional proteins of interest. Using the former, we constructed de novo a functional analog of AvrHah1 of Xanthomonas gardneri. The complete plasmid set is available through the non-profit repository AddGene and a web-based version of our software is freely accessible online.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Res
                Journal ID (iso-abbrev): Cell Res
                Title: Cell Research
                Publisher: Nature Publishing Group
                ISSN (Print): 1001-0602
                ISSN (Electronic): 1748-7838
                Publication date (Print): May 2014
                Publication date (Electronic): 25 March 2014
                Publication date PMC-release: 1 May 2014
                Volume: 24
                Issue: 5
                Pages: 513-531
                Affiliations
                [1 ]State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology , 320 Yueyang Road, Shanghai 200031, China
                [2 ]Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , 320 Yueyang Road, Shanghai 200031, China
                [3 ]Changzheng Hospital, Second Military Medical University , 415 Fengyang Road, Shanghai 200003, China
                Author notes
                Article
                Publisher Item ID: cr201435
                DOI: 10.1038/cr.2014.35
                PMC ID: 4011346
                PubMed ID: 24662484
                SO-VID: 19c9d1e4-74c0-4195-b6ed-21c794002240
                Copyright © Copyright © 2014 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
                License:

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0

                History
                Date received : 17 December 2013
                Date revision received : 06 January 2013
                Date accepted : 27 January 2012
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Cell biology
                Keywords: ccat1-l lncrna,super-enhancer,chromatin looping,myc,ctcf
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: ccat1-l lncrna, super-enhancer, chromatin looping, myc, ctcf

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