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      Loss of LSD1 (lysine-specific demethylase 1) suppresses growth and alters gene expression of human colon cancer cells in a p53- and DNMT1(DNA methyltransferase 1)-independent manner

      research-article
      Author(s): * , * , * , * , † , * , ‡ , * , 1
      Publication date (Electronic):
      Journal: Biochemical Journal
      Publisher: Portland Press Ltd.
      Keywords: chromatin, epigenetics, FAD-dependent oxidase, histone modification, transcriptional repression, AAV, adeno-associated viral, AOL, amine oxidase-like, ATRA, all-trans retinoic acid, ChIP, chromatin immunoprecipitation, COBRA, combined bisulfite restriction analysis, CoREST, RE1-silencing transcription factor corepressor 1, DNMT1, DNA methyltransferase 1, ES, embryonic stem, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, HA, homology arm, HDAC, histone deacetylase, HEK, human embryonic kidney, H3K4, histone H3 Lys4, H3K9, histone H3 Lys9, H3K9ac, H3K9 acetylation, JARID1, Jumonji, AT rich interactive domain 1, LINE-1, long interspersed nucleotide element 1, LSD, lysine-specific demethylase, me1, monomethyl, me2, dimethyl, me3, trimethyl, pAAV, AAV plasmid, PCNA, proliferating cell nuclear antigen, qPCR, quantitative PCR, SEPT, synthetic exon promoter trap, SET7/9, SET domain-containing histone methyltransferase 7/9, SWIRM, Swi3p/Rsc8p/Moira, TSS, transcriptional start site, VAT1L, vesicle amine transport protein 1 homologue-like, VIM, vimentin

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          Abstract

          Epigenetic silencing of gene expression is important in cancer. Aberrant DNA CpG island hypermethylation and histone modifications are involved in the aberrant silencing of tumour-suppressor genes. LSD1 (lysine-specific demethylase 1) is a H3K4 (histone H3 Lys 4) demethylase associated with gene repression and is overexpressed in multiple cancer types. LSD1 has also been implicated in targeting p53 and DNMT1 (DNA methyltransferase 1), with data suggesting that the demethylating activity of LSD1 on these proteins is necessary for their stabilization. To examine the role of LSD1 we generated LSD1 heterozygous ( LSD1 +/− ) and homozygous ( LSD1 −/− ) knockouts in the human colorectal cancer cell line HCT116. The deletion of LSD1 led to a reduced cell proliferation both in vitro and in vivo. Surprisingly, the knockout of LSD1 in HCT116 cells did not result in global increases in its histone substrate H3K4me2 (dimethyl-H3K4) or changes in the stability or function of p53 or DNMT1. However, there was a significant difference in gene expression between cells containing LSD1 and those null for LSD1. The results of the present study suggested that LSD1 is critical in the regulation of cell proliferation, but also indicated that LSD1 is not an absolute requirement for the stabilization of either p53 or DNMT1.

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          A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements.

          Allen Yang, Marcos R H Estécio, Ketan Doshi … (2004)
          We report a method for studying global DNA methylation based on using bisulfite treatment of DNA and simultaneous PCR of multiple DNA repetitive elements, such as Alu elements and long interspersed nucleotide elements (LINE). The PCR product, which represents a pool of approximately 15 000 genomic loci, could be used for direct sequencing, selective restriction digestion or pyrosequencing, in order to quantitate DNA methylation. By restriction digestion or pyrosequencing, the assay was reproducible with a standard deviation of only 2% between assays. Using this method we found that almost two-thirds of the CpG methylation sites in Alu elements are mutated, but of the remaining methylation target sites, 87% were methylated. Due to the heavy methylation of repetitive elements, this assay was especially useful in detecting decreases in DNA methylation, and this assay was validated by examining cell lines treated with the methylation inhibitor 5-aza-2'deoxycytidine (DAC), where we found a 1-16% decrease in Alu element and 18-60% LINE methylation within 3 days of treatment. This method can be used as a surrogate marker of genome-wide methylation changes. In addition, it is less labor intensive and requires less DNA than previous methods of assessing global DNA methylation.
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            Model-based variance-stabilizing transformation for Illumina microarray data

            Simon M Lin, Pan Du, Wolfgang Huber … (2008)
            Variance stabilization is a step in the preprocessing of microarray data that can greatly benefit the performance of subsequent statistical modeling and inference. Due to the often limited number of technical replicates for Affymetrix and cDNA arrays, achieving variance stabilization can be difficult. Although the Illumina microarray platform provides a larger number of technical replicates on each array (usually over 30 randomly distributed beads per probe), these replicates have not been leveraged in the current log2 data transformation process. We devised a variance-stabilizing transformation (VST) method that takes advantage of the technical replicates available on an Illumina microarray. We have compared VST with log2 and Variance-stabilizing normalization (VSN) by using the Kruglyak bead-level data (2006) and Barnes titration data (2005). The results of the Kruglyak data suggest that VST stabilizes variances of bead-replicates within an array. The results of the Barnes data show that VST can improve the detection of differentially expressed genes and reduce false-positive identifications. We conclude that although both VST and VSN are built upon the same model of measurement noise, VST stabilizes the variance better and more efficiently for the Illumina platform by leveraging the availability of a larger number of within-array replicates. The algorithms and Supplementary Data are included in the lumi package of Bioconductor, available at: www.bioconductor.org.
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              Opposing LSD1 complexes function in developmental gene activation and repression programmes.

              Jianxun Wang, Kathleen Scully, Xiaoyan Zhu … (2007)
              Precise control of transcriptional programmes underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies. One thing that remains unclear is how specific members of histone modification enzyme families, such as histone methyltransferases and demethylases, are used in vivo to simultaneously orchestrate distinct developmental gene activation and repression programmes. Here, we report that the histone lysine demethylase, LSD1--a component of the CoREST-CtBP co-repressor complex--is required for late cell-lineage determination and differentiation during pituitary organogenesis. LSD1 seems to act primarily on target gene activation programmes, as well as in gene repression programmes, on the basis of recruitment of distinct LSD1-containing co-activator or co-repressor complexes. LSD1-dependent gene repression programmes can be extended late in development with the induced expression of ZEB1, a Krüppel-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CoREST-CtBP co-repressor complex, causing repression of an additional cohort of genes, such as Gh, which previously required LSD1 for activation. These findings suggest that temporal patterns of expression of specific components of LSD1 complexes modulate gene regulatory programmes in many mammalian organs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biochem J
                Journal ID (iso-abbrev): Biochem. J
                Journal ID (pmc): bic
                Journal ID (publisher-id): BJ
                Title: Biochemical Journal
                Publisher: Portland Press Ltd.
                ISSN (Print): 0264-6021
                ISSN (Electronic): 1470-8728
                Publication date (Electronic preprint): 17 October 2012
                Publication date (Electronic): 14 December 2012
                Publication date (Print): 15 January 2013
                Volume: 449
                Issue: Pt 2
                Pages: 459-468
                Affiliations
                *The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, U.S.A.
                †Predoctoral Training Program in Human Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, U.S.A.
                ‡Department of Drug Discovery and Biomedical Sciences, The Medical University of South Carolina, Charleston, SC 29425, U.S.A.
                Author notes
                1To whom correspondence should be addressed (email rcasero@ 123456jhmi.edu ).
                Article
                Publisher ID: BJ20121360
                DOI: 10.1042/BJ20121360
                PMC ID: 3525012
                PubMed ID: 23072722
                SO-VID: 4f27813f-d03b-411f-b4c5-1f9166af521f
                Copyright © © 2013 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 28 August 2012
                Date revision received : 15 October 2012
                Date accepted : 17 October 2012
                Page count
                Figures: 7, References: 45, Pages: 10
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Biochemistry
                Keywords: chromatin,epigenetics,fad-dependent oxidase,histone modification,transcriptional repression,aav, adeno-associated viral,aol, amine oxidase-like,atra, all-trans retinoic acid,chip, chromatin immunoprecipitation,cobra, combined bisulfite restriction analysis,corest, re1-silencing transcription factor corepressor 1,dnmt1, dna methyltransferase 1,es, embryonic stem,gapdh, glyceraldehyde-3-phosphate dehydrogenase,ha, homology arm,hdac, histone deacetylase,hek, human embryonic kidney,h3k4, histone h3 lys4,h3k9, histone h3 lys9,h3k9ac, h3k9 acetylation,jarid1, jumonji, at rich interactive domain 1,line-1, long interspersed nucleotide element 1,lsd, lysine-specific demethylase,me1, monomethyl,me2, dimethyl,me3, trimethyl,paav, aav plasmid,pcna, proliferating cell nuclear antigen,qpcr, quantitative pcr,sept, synthetic exon promoter trap,set7/9, set domain-containing histone methyltransferase 7/9,swirm, swi3p/rsc8p/moira,tss, transcriptional start site,vat1l, vesicle amine transport protein 1 homologue-like,vim, vimentin
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: chromatin, epigenetics, fad-dependent oxidase, histone modification, transcriptional repression, aav, adeno-associated viral, aol, amine oxidase-like, atra, all-trans retinoic acid, chip, chromatin immunoprecipitation, cobra, combined bisulfite restriction analysis, corest, re1-silencing transcription factor corepressor 1, dnmt1, dna methyltransferase 1, es, embryonic stem, gapdh, glyceraldehyde-3-phosphate dehydrogenase, ha, homology arm, hdac, histone deacetylase, hek, human embryonic kidney, h3k4, histone h3 lys4, h3k9, histone h3 lys9, h3k9ac, h3k9 acetylation, jarid1, jumonji, at rich interactive domain 1, line-1, long interspersed nucleotide element 1, lsd, lysine-specific demethylase, me1, monomethyl, me2, dimethyl, me3, trimethyl, paav, aav plasmid, pcna, proliferating cell nuclear antigen, qpcr, quantitative pcr, sept, synthetic exon promoter trap, set7/9, set domain-containing histone methyltransferase 7/9, swirm, swi3p/rsc8p/moira, tss, transcriptional start site, vat1l, vesicle amine transport protein 1 homologue-like, vim, vimentin

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