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      Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

      Author(s): , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
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      Journal: Nature Medicine
      Publisher: Springer Nature

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          Abstract

          Inactivating mutations in ACTRT1 or surrounding noncoding sequences transcribed into functional enhancer RNAs cause aberrant activation of Hedgehog signaling in both sporadic and inherited forms, such as Bazex–Dupré–Christol syndrome, of basal cell carcinoma. These findings identify a new tumor-suppressor gene and underscore the functional relevance of genomic alterations in noncoding transcribed regions in tumor development.

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          ChIP-seq accurately predicts tissue-specific activity of enhancers.

          Axel Visel, Matthew J. Blow, Zirong Li … (2009)
          A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover because they are scattered among the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here we present the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggest that such data sets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale.
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            LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

            Liuqing Yang, Chunru Lin, Chunyu Jin … (2013)
            While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.
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              Genomic Views of Distant-Acting Enhancers

              Axel Visel, Edward M. Rubin, Len Pennacchio (2009)
              Preface In contrast to changes in protein-coding sequences, the significance of noncoding DNA variation in human disease has been minimally explored. A recent torrent of genome-wide association studies suggests that noncoding variation represents a significant risk factor for common disorders, but the mechanisms by which they contribute to disease remain largely obscure. Distant-acting transcriptional enhancers - a major category of functional noncoding DNA - are likely involved in many developmental and disease-relevant processes. Genome-wide approaches for their discovery and functional characterization are now available and provide a growing knowledgebase for the systematic exploration of their role in human biology and disease susceptibility.
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                Author and article information

                Journal
                Title: Nature Medicine
                Abbreviated Title: Nat Med
                Publisher: Springer Nature
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Created: September 4 2017
                Publication date (Print): September 4 2017
                Volume:
                Issue:
                Article
                DOI: 10.1038/nm.4368
                PubMed ID: 28869610
                SO-VID: af38cb04-0490-48c0-89ee-9b65fe343bc0
                Copyright © © 2017
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