Daniel Group – University of Copenhagen

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Daniel Group - Chromatin Structure & Function

First row from left: Su Dan, Jeremy Daniel, Andrea Mund (now in Mann group), Rebeca Soria and Andreas Ingham

The Chromatin Structure & Function research group  is headed by Dr. Jeremy A. Daniel and started its activities at CPR in January 2012.

The mission of our laboratory is to identify therapeutic targets for cancer by investigating basic mechanisms for how dynamic chromatin environments impact the stability of our genomes. DNA double-strand breaks (DSBs) can be caused by exogenous damage or collapsed replication forks. The double-strand breaks also transiently occur during normal physiology as part of programmed DNA rearrangements in lymphocytes called V(D)J recombination and class-switch recombination. Once damaged, a DNA lesion such as a DSB must first be made accessible by changes in chromatin structure to allow for subsequent DNA repair to occur. A better physiological understanding of how cells repair their DNA within the context of chromatin holds the potential to promote or suppress the efficiency of DNA repair, with implications for healthy aging, cancer prevention, and for sensitizing cancer cells to therapeutic agents.

Despite our understanding of the role of chromatin in transcriptional regulation, the consequences of changes in chromatin structure and post-translational modifications that directly affect the stability of our genomes to suppress cancer remain surprisingly unclear. A number of enzymes that catalyze post-translational acetylation and methylation of proteins have been identified and characterized based on their substrate specificity for the histone protein components of chromatin and usually exist in multi-subunit complexes. Recent genome, exome, and RNA sequencing efforts have established that a number of post-translational histone modifiers are significantly mutated in cancer. Our approach is to utilize mice as a physiological model together with a combination of biochemistry, flow cytometry, genomics, and proteomics for investigating how protein complexes that modify or associate with chromatin regulate genomic stability and prevent lymphoid malignancy. We are also interested in understanding how transcription and DSB repair can influence each other and how this coordination occurs within the context of chromatin.

To interrogate how chromatin modifying activities coordinate transcription and DSB repair, one interest of our lab is the class-switch recombination reaction that occurs in B lymphocytes at the immunoglobulin heavy-chain locus. Lymphocytes of our immune system have evolved to tolerate additional DNA damage in order to generate antibody diversity with the appropriate isotype and affinity for the successful clearance of pathogens from our body. Chromatin accessibility and transcription of an antigen receptor gene segment are essential features of the targeting mechanism for DSB formation during V(D)J and and class-switch recombination and a failure to resolve unrepaired DSBs during these reactions can lead to immunodeficiency and the formation of oncogenic chromosomal translocations. To understand how dynamic changes in chromatin structure impact the stability of our genomes and suppress cancer, proteomic screens for chromatin-interacting factors and chromatin modifying complexes will be used in combination with targeted gene inactivation in mice.

Sapere Aude Grant to Jeremy A. Daniel

In January 2013 Jeremy A. Daniel was awarded the prestigious Sapere Aude grant from The Danish Council for Independent Research for his pioneering research project focusing on understanding how DNA patterns are generated and controlled during development of healthy and cancerous white blood cells. Click for more information on the project.

Selected publications

Smith EA, Gole B, Willis NA, Soria R, Starnes LM, Krumpelbeck EF, Jegga AG, Ali AM, Guo H, Meetei AR, Andreassen PR, Kappes F, Vinnedge LM, Daniel JA, Scully R, Wiesmüller L, Wells SI. DEK is required for homologous recombination repair of DNA breaks. Sci Rep, 2017 Mar 20;7:44662.
Hansen RK*, Mund A*, Poulsen SL*, Sandoval M, Tsouroula K, Klement K, Tollenaere MA, Räschle M, Soria R, Offermanns S, Worzfeld T, Grosse R, Brandt DT, Rozell B, Mann M, Cole F, Soutoglou E, Goodarzi AA, Daniel JA#, Mailand N#, Bekker-Jensen S#.  SCAI promotes DNA double-strand break repair in distinct chromosomal contexts. Nature Cell Biology, 2016 Dec;18(12):1357-1366.  *co-first authors, #co-corresponding authors
Larsen SC, Sylvestersen KB, Mund A, Mullari M, Madsen MV, Lyon D, Daniel JA, Jensen LJ, Nielsen ML. Proteome-wide analysis of arginine methylation reveals wide-spread occurrence in human cells. Science Signaling, 2016 Aug 30;9(443)rs9.  
Kristiansen TA, Gyllenback EJ, Zriwil A, Bjorklund T, Daniel JA, Sitnicka E, Soneji S, Bryder D, Yuan J. Cellular barcoding links B-1a B cell potential to a reversible fetal hematopoietic stem cell state at the clonal level. Immunity, 2016 Aug 16;45(2):346-357.  
Chaudhuri AR, Callen E, Ding X, Gogola, Duarte AA, Lee JE, Wong N, Lafarga V, Calvo JA, Panzarino NJ, John S, Day A, Crespo AV, Chen HT, Shen B, Starnes LM, Daniel JA, de Ruiter JR, Konstantinopoulos PA, Cortez D, Cantor SB, Fernandez-Capetillo O, Ge K, Jonkers J, Rottenberg S, Sharan S, Nussenzweig A. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature, 2016 Jul 20;535(7612):382-7. 

Starnes LM, Su D, Pikkupeura LM, Weinert BT, Sanots MA, Mund A, Soria R, Cho YW, Pozdnyakova I, Kubec Højfeldt M, Vala A, Yang W, Lopez-Mendez B, Lee JE, Peng W, Yuan J, Ge K, Montoya G, Nussenzweig A, Choudhary C, Daniel JA. A PTIP-PA1 subcomplex promotes transcription for IgH class-switching independently from the associated MLL3/MLL4 methyltransferase complex. Genes & Development, 2016 Jan 15;30(2):149-63.

Weinert BT, Scholz C, Wagner SA, Iesmantavicius V, Su D, Daniel JA, Choudhary C. Lysine succinylation is a frequently occurring posttranslational modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Reports, 2013 Aug 29;4(4):842-51.

Callen E, Di Virgilio M, Kruhlak MJ, Nieto-Soler M, Wong N, Chen HT, Faryabi RB, Polato F, Santos M, Starnes LM, Wesemann DR, Lee J-E, Tubbs A, Daniel JA, Sleckman BP, Ge K, Alt FW, Fernandez-Capetillo O, Nussenzweig MC, Nussenzweig A. 53BP1 mediates productive and mutagenic DNA repair through distinct phospho-protein interactions. Cell, 2013 Jun 6;153(6):1266-80.

Daniel JA*, Nussenzweig A*. The AID-induced DNA damage response in chromatin. Mol Cell, 2013 May 9;50(3):309-21. *co-corresponding authors

Callen E, Faryabi R, Hao B, Daniel JA, Yang W, Chi H, Dressler GR, Luckey M, Peng W, Krangel MS, Park JH, Nussenzweig A. The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration. Immunity, 2012 Dec 14;37(6):971-85.

Daniel JA*, Pellegrini M, Lee BS, Guo Z, Filsuf D, Belkina NV, You Z, Paull TT, Sleckman BP, Feigenbaum L, Nussenzweig A*. Loss of ATM kinase activity leads to embryonic lethality in mice. J Cell Biol. 2012 Aug 6;198(3):295-304. *co-corresponding authors. 

Daniel JA*, Nussenzweig A*. Roles for histone H3K4 methyltransferase activities during immunoglobulin class-switch recombination. Biochim Biophys Acta 2012 Jul;1819(7):733-8. *co-corresponding authors

Daniel JA, Santos MA, Wang Z, Zang C, Schwab KR, Jankovic M, Filsuf D, Chen HT, Gazumyan A, Yamane A, Cho YW, Sun HW, Ge K, Peng W, Nussenzweig MC, Casellas R, Dressler GR, Zhao K, Nussenzweig A. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science 2010 Aug 20;329(5994): 917-23. 

Daniel JA*, Pellegrini M*, Lee JH, Paull TT, Feigenbaum L, Nussenzweig A. Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo. J Cell Biol. 2008 Dec 1;183(5):777-83. *authors contributed equally

Callen E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A, Pellegrini M, McBride K, Wangsa D, Bredemeyer AL, Sleckman BP, Ried T, Nussenzweig MC, Nussenzweig A. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell 2007 Jul 13;130(1): 63-75.

Pray-Grant MG, Daniel JA, Schieltz D, Yates JR 3rd, Grant PA. Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation. Nature. 2005 Jan 27;433(7024):434-8.