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      LSD1: biologic roles and therapeutic targeting

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          Abstract

          LSD1 (KDM1A; BHC110; AOF2) was the first protein reported to exhibit histone demethylase activity and has since been shown to have multiple essential roles in mammalian biology. Given its enzymatic activity and its high-level expression in many human malignancies, a significant recent focus has been the development of pharmacologic inhibitors. Here we summarize structural and biochemical knowledge of this important epigenetic regulator, with a particular emphasis on the functional and preclinical studies in oncology that have provided justification for the evaluation of tranylcypromine derivative LSD1 inhibitors in early phase clinical trials.

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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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            Immunogenetics. Chromatin state dynamics during blood formation.

            David Lara-Astiaso, Assaf Weiner, Erika Lorenzo-Vivas … (2014)
            Chromatin modifications are crucial for development, yet little is known about their dynamics during differentiation. Hematopoiesis provides a well-defined model to study chromatin state dynamics; however, technical limitations impede profiling of homogeneous differentiation intermediates. We developed a high-sensitivity indexing-first chromatin immunoprecipitation approach to profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation. We identify 48,415 enhancer regions and characterize their dynamics. We find that lineage commitment involves de novo establishment of 17,035 lineage-specific enhancers. These enhancer repertoire expansions foreshadow transcriptional programs in differentiated cells. Combining our enhancer catalog with gene expression profiles, we elucidate the transcription factor network controlling chromatin dynamics and lineage specification in hematopoiesis. Together, our results provide a comprehensive model of chromatin dynamics during development. Copyright © 2014, American Association for the Advancement of Science.
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              Functional annotation of native enhancers with a Cas9 -histone demethylase fusion

              Nicola A Kearns, Hannah Pham, Barbara Tabak … (2015)
              Understanding of mammalian enhancer function is limited by the lack of a technology to rapidly and thoroughly test their cell type-specific function. Here, we use a nuclease-deficient (d)Cas9 histone demethylase fusion to functionally characterize previously described and novel enhancer elements for their roles in the embryonic stem cell state. Further, we distinguish the mechanism of action of dCas9-LSD1 at enhancers from previous dCas9-effectors.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Epigenomics
                Journal ID (iso-abbrev): Epigenomics
                Journal ID (publisher-id): EPI
                Title: Epigenomics
                Publisher: Future Medicine Ltd (London, UK )
                ISSN (Print): 1750-1911
                ISSN (Electronic): 1750-192X
                Publication date (Print): August 2016
                Publication date (Electronic): 01 August 2016
                Volume: 8
                Issue: 8
                Pages: 1103-1116
                Affiliations
                [1 ]Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK
                Author notes
                Article
                DOI: 10.2217/epi-2016-0009
                PMC ID: 5066116
                PubMed ID: 27479862
                SO-VID: 9a724e74-39d6-4504-b174-03b6701ffc69
                Copyright © © A Maiques-Diaz & TCP Somervaille
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License

                History
                Date received : 25 January 2016
                Date accepted : 27 May 2016
                Categories
                Subject: Review

                Keywords: acute myeloid leukemia,gsk2879552,histone demethylase,lsd1,ory1001,small-cell lung cancer
                Data availability:
                Keywords: acute myeloid leukemia, gsk2879552, histone demethylase, lsd1, ory1001, small-cell lung cancer

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