For animals to survive, they must adapt to new environments. Depending on nutrient availability, they adjust their growth, cell morphology and behavior. And different cell-types within the animal show unique responses to nutrient levels in order to aid survival. Often these specific cells exist in a matrix of cell-types that are not easily separated. For example, the pancreas and the brain both exhibit vital but distinct responses to nutrient availability and they are histologically composed of a matrix of different cell-types. The open challenge in our field is thus to understand how gene expression adapts genome-wide within individual cell-types in complex cell matrices. In our BioSysNet project, we take advantage of novel genetic tools that we have engineered to study how changes in metabolism generate distinct gene expression responses within specific cell-types in a living organism and dissect the epigenetic mechanisms that underlie these physiological adaptations.

We build on our interest in the control of gene expression by applying genetically-encoded tools in the powerful model Drosophila melanogaster to study how starvation and re-feeding alter chromatin dynamics and gene expression within highly specialized cell-types. We exploit existing and new genomic approaches, together with bioinformatics and modeling, to profile chromatin structure, histone variants and histone modifications, transcription and mRNA-levels within different cell-types and upon metabolic perturbation. This will allow us to obtain genome-wide and cell-type specific insight into how metabolic changes drive epigenetic and gene expression plasticity.

This BioSysNet project merges our interests at the interface of metabolism, genomics and epigenetics through a genomics-driven dissection of a physiological process, complementary to ongoing proteomic analyses of metabolism. Our long-range objectives are to identify, dissect and model epigenetic and transcriptional mechanisms that govern an organism’s systemic response to the environment giving us insight into how altered nutrient levels coordinate changes in gene and cell networks.

Dr. Carla Margulies

Jyaysi Desai

Ava Handley

Tamas Schauer

Schauer T, Schwalie PC, Handley A, Margulies CE, Flicek P, Ladurner AG (2013). CAST-ChIP maps cell-type-specific chromatin states in the Drosophila central nervous system. Cell Rep 5(1):271-82. 

The chaperone-histone partnership: for the greater good of histone traffic and chromatin plasticity. Hondele M, Ladurner AG. Curr Opin Struct Biol. 2011 Nov 2.

PARG: A Macrodomain in Disguise. Hassler M, Jankevicius G, Ladurner AG. Structure. 2011 Oct 12;19(10):1351-3.

Structural basis for the role of the Sir3 AAA+ domain in silencing: interaction with Sir4 and unmethylated histone H3K79. Ehrentraut S, Hassler M, Oppikofer M, Kueng S, Weber JM, Mueller JW, Gasser SM, Ladurner AG, Ehrenhofer-Murray AE. Genes Dev. 2011 Sep 1;25(17):1835-46.

Stress-Induced PARP Activation Mediates Recruitment of Drosophila Mi-2 to Promote Heat Shock Gene Expression. Murawska M, Hassler M, Renkawitz-Pohl R, Ladurner AG, Brehm A. PLoS Genet. 2011 Jul;7(7):e1002206.

A mitotic beacon reveals its nucleosome anchor. Hondele M, Ladurner AG. Mol Cell. 2010 Sep 24;39(6):829-30.

SirT1 in muscle physiology and disease: lessons from mouse models. Vinciguerra M, Fulco M, Ladurner AG, Sartorelli V, Rosenthal N. Dis Model Mech. 2010 May-Jun;3(5-6):298-303.

A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Timinszky G, Till S, Hassa PO, Hothorn M, Kustatscher G, Nijmeijer B, Colombelli J, Altmeyer M, Stelzer EH, Scheffzek K, Hottiger MO, Ladurner AG. Nat Struct Mol Biol. 2009 Sep;16(9):923-9.

Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK, Washburn MP, Florens L, Ladurner AG, Conaway JW, Conaway RC. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13770-4.

Repression of RNA polymerase II transcription by a Drosophila oligopeptide. Timinszky G, Bortfeld M, Ladurner AG. PLoS One. 2008 Jun 25;3(6):e2506.

Histone macroH2A isoforms predict the risk of lung cancer recurrence. Sporn JC, Kustatscher G, Hothorn T, Collado M, Serrano M, Muley T, Schnabel P, Ladurner AG. Oncogene. 2009 Sep 24;28(38):3423-8.

Chromatin places metabolism center stage. Ladurner AG. Cell. 2009 Jul 10;138(1):18-20.

Catalytic core of a membrane-associated eukaryotic polyphosphate polymerase. Hothorn M, Neumann H, Lenherr ED, Wehner M, Rybin V, Hassa PO, Uttenweiler A, Reinhardt M, Schmidt A, Seiler J, Ladurner AG, Herrmann C, Scheffzek K, Mayer A. Science. 2009 Apr 24;324(5926):513-6.

Sensing NAD metabolites through macro domains. Till S, Ladurner AG. Front Biosci. 2009 Jan 1;14:3246-58.

Combining affinity purification by ADP-ribose-binding macro domains with mass spectrometry to define the mammalian ADP-ribosyl proteome. Dani N, Stilla A, Marchegiani A, Tamburro A, Till S, Ladurner AG, Corda D, Di Girolamo M. Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4243-8.

Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity. Vinciguerra M, Santini MP, Claycomb WC, Ladurner AG, Rosenthal N. Aging (Albany NY). 2009 Dec 10;2(1):43-62.

N terminus of Swr1 binds to histone H2AZ and provides a platform for subunit assembly in the chromatin remodeling complex. Wu WH, Wu CH, Ladurner AG, Mizuguchi G, Wei D, Xiao H, Luk E, Ranjan A, Wu C. J Biol Chem. 2009 Mar 6; 284(10):6200-7.

PARP: a transferase by any other name. Till S, Diamantara K, Ladurner AG. Nat Struct Mol Biol. 2008 Dec;15(12):1243-4.

The FACT Spt16 "peptidase" domain is a histone H3-H4 binding module. Stuwe T, Hothorn M, Lejeune E, Rybin V, Bortfeld M, Scheffzek K, Ladurner AG. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8884-9.

Repression of RNA polymerase II transcription by a Drosophila oligopeptide. Timinszky G, Bortfeld M, Ladurner AG. PLoS One. 2008 Jun 25;3(6):e2506.

A metabolic throttle regulates the epigenetic state of rDNA. Grummt I, Ladurner AG. Cell. 2008 May 16;133(4):577-80.

RNA Pol IV plays catch with Argonaute 4. Till S, Ladurner AG. Cell. 2007 Nov 16 ; 131 (4):643-5.

An acetylation switch in p53 mediates holo-TFIID recruitment. Li AG, Piluso LG, Cai X, Gadd BJ, Ladurner AG, Liu X. Mol Cell. 2007 Nov 9;28(3):408-21.

Modular paths to 'decoding' and 'wiping' histone lysine methylation. Kustatscher G, Ladurner AG. Curr Opin Chem Biol. 2007 Dec;11(6):628-35.

A conserved motif in Argonaute-interacting proteins mediates functional interactions through the Argonaute PIWI domain. Till S, Lejeune E, Thermann R, Bortfeld M, Hothorn M, Enderle D, Heinrich C, Hentze MW, Ladurner AG. Nat Struct Mol Biol. 2007 Oct;14(10):897-903.

Co-localization of CENP-C and CENP-H to discontinuous domains of CENP-A chromatin at human neocentromeres. Alonso A, Fritz B, Hasson D, Abrusan G, Cheung F, Yoda K, Radlwimmer B, Ladurner AG, Warburton PE. Genome Biol. 2007;8 (7):R148.

The chromatin-remodeling factor FACT contributes to centromeric heterochromatin independently of RNAi. Lejeune E, Bortfeld M, White SA, Pidoux AL, Ekwall K, Allshire RC, Ladurner AG. Curr Biol. 2007 Jul 17;17(14):1219-24.

Rheostat control of gene expression by metabolites. Ladurner AG. Mol Cell. 2006 Oct 6;24(1):1-11.

Splicing regulates NAD metabolite binding to histone macroH2A. Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG. Nat Struct Mol Biol. 2005 Jul;12 (7): 624-5.

The macro domain is an ADP-ribose binding module. Karras GI, Kustatscher G, Buhecha HR, Allen MD, Pugieux C, Sait F, Bycroft M, Ladurner AG. EMBO J. 2005 Jun 1;24(11):1911-20.

Hitting transcription in all the right places. Lejeune E, Ladurner AG. Nat Struct Mol Biol. 2005 May;12(5):390-2.

Inactivating chromosomes: a macro domain that minimizes transcription. Ladurner AG. Mol Cell. 2003 Jul;12(1):1-3.

Bromodomains mediate an acetyl-histone encoded antisilencing function at heterochromatin boundaries. Ladurner AG, Inouye C, Jain R, Tjian R. Mol Cell. 2003 Feb;11(2):365-76.

Tick-tock goes the acetylation clock. Ladurner AG. Nat Struct Biol. 2003 Feb;10(2):83.

Mutations of penicillin acylase residue B71 extend substrate specificity by decreasing steric constraints for substrate binding. Morillas M, McVey CE, Brannigan JA, Ladurner AG, Forney LJ, Virden R. Biochem J. 2003 Apr 1;371(Pt 1):143-50.

From an armadillo to electricity. Ladurner AG. Nat Struct Biol. 2003 Jan;10(1):12.

Picture story. Sabotage through structural mimicry. Ladurner AG. Nat Struct Biol. 2002 Dec;9(12):899.

The origin of silence. Ladurner AG. Nat Struct Biol. 2002 Oct;9(10):718.

Structure and function of a human TAFII250 double bromodomain module. Jacobson RH, Ladurner AG, King DS, Tjian R. Science. 2000 May 26;288(5470):1422-5.

Three-dimensional structure of the human TFIID-IIA-IIB complex. Andel F 3rd, Ladurner AG, Inouye C, Tjian R, Nogales E. Science. 1999 Dec 10;286(5447):2153-6.

The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Ryu S, Zhou S, Ladurner AG, Tjian R. Nature. 1999 Feb 4;397 (6718):446-50.

Upper limit of the time scale for diffusion and chain collapse in chymotrypsin inhibitor 2. Ladurner AG, Fersht AR. Nat Struct Biol. 1999 Jan;6(1):28-31.

Synergy between simulation and experiment in describing the energy landscape of protein folding. Ladurner AG, Itzhaki LS, Daggett V, Fersht AR.Proc Natl Acad Sci USA. 1998 Jul 21;95(15):8473-8.

Glutamine, alanine or glycine repeats inserted into the loop of a protein have minimal effects on stability and folding rates. Ladurner AG, Fersht AR. J Mol Biol. 1997 Oct 17;273(1):330-7.

Complementation of peptide fragments of the single domain protein chymotrypsin inhibitor 2. Ladurner AG, Itzhaki LS, de Prat Gay G, Fersht AR. J Mol Biol. 1997 Oct17; 273(1):317-29.

Following co-operative formation of secondary and tertiary structure in a single protein module. Neira JL, Itzhaki LS, Ladurner AG, Davis B, de Prat Gay G, Fersht AR. J Mol Biol. 1997 Apr 25;268(1):185-97.

Strain in the folding nucleus of chymotrypsin inhibitor 2. Ladurner AG, Itzhaki LS, Fersht AR. Fold Des. 1997;2(6):363-8.

Towards the complete structural characterization of a protein folding pathway: the structures of the denatured, transition and native states for the association/folding of two complementary fragments of cleaved chymotrypsin inhibitor 2. Direct evidence for a nucleation-condensation mechanism. Neira JL, Davis B, Ladurner AG, Buckle AM, Gay Gde P, Fersht AR. Fold Des. 1996;1(3):189-208.

Conformational pathway of the polypeptide chain of chymotrypsin inhibitor-2 growing from its N terminus in vitro. Parallels with the protein folding pathway. de Prat Gay G, Ruiz-Sanz J, Neira JL, Corrales FJ, Otzen DE, Ladurner AG, Fersht AR. J Mol Biol. 1995 Dec 15;254(5):968-79.