Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells

Under the instruction of cell-fate–determining, DNA-binding transcription factors, chromatin-modifying enzymes mediate and maintain cell states throughout development in multicellular organisms. Currently, small molecules modulating the activity of several classes of chromatin-modifying enzymes are available, including clinically approved histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors. We describe the genome-wide expression changes induced by 29 compounds targeting HDACs, DNMTs, histone lysine methyltransferases (HKMTs), and protein arginine methyltransferases (PRMTs) in pancreatic α- and β-cell lines. HDAC inhibitors regulate several hundred transcripts irrespective of the cell type, with distinct clusters of dissimilar activity for hydroxamic acids and orthoamino anilides. In contrast, compounds targeting histone methyltransferases modulate the expression of restricted gene sets in distinct cell types. For example, we find that G9a/GLP methyltransferase inhibitors selectively up-regulate the cholesterol biosynthetic pathway in pancreatic but not liver cells. These data suggest that, despite their conservation across the entire genome and in different cell types, chromatin pathways can be targeted to modulate the expression of selected transcripts.

[1]  Peter A. DiMaggio,et al.  A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. , 2011, Nature chemical biology.

[2]  S. Schreiber,et al.  Discovery of histone deacetylase 8 selective inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[3]  Jasmine Zain,et al.  Romidepsin in the treatment of cutaneous T-cell lymphoma , 2011, Journal of blood medicine.

[4]  C. Allis,et al.  Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers , 2010, Nature Reviews Cancer.

[5]  Tomohiro Kono,et al.  Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells , 2010, Nature.

[6]  M. Sodeoka,et al.  Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. , 2010, Journal of the American Chemical Society.

[7]  James E. Bradner,et al.  Chemical Phylogenetics of Histone Deacetylases , 2010, Nature chemical biology.

[8]  A. Means,et al.  Faculty Opinions recommendation of The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. , 2009 .

[9]  O. Madsen,et al.  The Ectopic Expression of Pax4 in the Mouse Pancreas Converts Progenitor Cells into α and Subsequently β Cells , 2009, Cell.

[10]  W-S Xu,et al.  Histone deacetylase inhibitors: Potential in cancer therapy , 2009, Journal of cellular biochemistry.

[11]  J. Issa,et al.  Targeting DNA Methylation , 2009, Clinical Cancer Research.

[12]  P. Barter,et al.  Cholesterol metabolism and pancreatic β-cell function , 2009, Current opinion in lipidology.

[13]  L. Benson,et al.  The anticancer agent chaetocin is a competitive substrate and inhibitor of thioredoxin reductase. , 2009, Antioxidants & redox signaling.

[14]  J. Snyder,et al.  Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294 , 2009, Nature Structural &Molecular Biology.

[15]  D. Melton,et al.  Extreme makeover: converting one cell into another. , 2008, Cell stem cell.

[16]  T. Litman,et al.  Molecular Cancer Differential Effects of Class I Isoform Histone Deacetylase Depletion and Enzymatic Inhibition by Belinostat or Valproic Acid in Hela Cells , 2022 .

[17]  R. Scharfmann,et al.  Histone Deacetylase Inhibitors Modify Pancreatic Cell Fate Determination and Amplify Endocrine Progenitors , 2008, Molecular and Cellular Biology.

[18]  P. Atadja,et al.  Histone Deacetylase Inhibitor Panobinostat Induces Clinical Responses with Associated Alterations in Gene Expression Profiles in Cutaneous T-Cell Lymphoma , 2008, Clinical Cancer Research.

[19]  A. Yoshimura,et al.  Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model , 2008, Molecular Cancer Therapeutics.

[20]  Joshua Close,et al.  Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2). , 2008, Bioorganic & medicinal chemistry letters.

[21]  Alyssa H. Hasty,et al.  Direct Effect of Cholesterol on Insulin Secretion , 2007, Diabetes.

[22]  P. Marks,et al.  Discovery and development of SAHA as an anticancer agent , 2007, Oncogene.

[23]  E. Lander,et al.  The Mammalian Epigenome , 2007, Cell.

[24]  Karl Mechtler,et al.  Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. , 2007, Molecular cell.

[25]  Bhaskar Ponugoti,et al.  Coordinated Recruitment of Histone Methyltransferase G9a and Other Chromatin-Modifying Enzymes in SHP-Mediated Regulation of Hepatic Bile Acid Metabolism , 2006, Molecular and Cellular Biology.

[26]  Michael Rowley,et al.  A series of novel, potent, and selective histone deacetylase inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[27]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[28]  J. Mesirov,et al.  GenePattern 2.0 , 2006, Nature Genetics.

[29]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Axel Imhof,et al.  Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9 , 2005, Nature chemical biology.

[31]  Frank Lyko,et al.  Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. , 2005, Cancer research.

[32]  Gordon K Smyth,et al.  Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[33]  P. Jones,et al.  Zebularine: a new drug for epigenetic therapy. , 2004, Biochemical Society transactions.

[34]  Randall W King,et al.  Small Molecule Regulators of Protein Arginine Methyltransferases* , 2004, Journal of Biological Chemistry.

[35]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[36]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[37]  K. Glaser,et al.  Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. , 2003, Molecular cancer therapeutics.

[38]  S. Schreiber,et al.  Signaling Network Model of Chromatin , 2002, Cell.

[39]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[40]  S. Schreiber,et al.  Genomewide studies of histone deacetylase function in yeast. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  K. Panchalingam,et al.  Analysis of a Chinese hamster ovary cell mutant with defective mobilization of cholesterol from the plasma membrane to the endoplasmic reticulum. , 1997, Journal of lipid research.

[42]  S. Efrat,et al.  Regulation of Insulin Secretion from β-Cell Lines Derived from Transgenic Mice Insulinomas Resembles that of Normal β-Cells* , 1990 .

[43]  Zachary D. Smith,et al.  Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses , 2009 .

[44]  Gordon K. Smyth,et al.  limma: Linear Models for Microarray Data , 2005 .

[45]  I. Talianidis,et al.  Functional role of G9a-induced histone methylation in small heterodimer partner-mediated transcriptional repression. , 2004, Nucleic acids research.

[46]  S. Efrat,et al.  Regulation of insulin secretion from beta-cell lines derived from transgenic mice insulinomas resembles that of normal beta-cells. , 1990, Endocrinology.