CONTACT

Peter Mulligan, Ph.D.

Chef d'équipe/Group Leader
Centre de Recherche en Cancérologie de Lyon (CRCL)
Centre Léon Bérard, Cheney A, 5e étage
28 rue Laennec
69373 Lyon, Cedex 08

Email: peter.mulligan@lyon.unicancer.fr

Tel.: +33 (0)4 69 85 60 72

MULLIGAN Peter
Chef d'équipe, Inserm CR1 Researcher
peter.mulligan@lyon.unicancer.fr

BARBOLLAT Laetitia
UCBL1 Assistant Ingenieur
laetitia.barbollat@lyon.unicancer.fr
SIOUDA Maha
UCBL1 Researcher/Postdoctoral Fellow
Maha.SIOUDA@lyon.unicancer.fr
BENAISSA Marine
DUJARDIN Audrey
DUFORESTEL MANON
Voir les objectifs et projets Voir les publications

 



OBJECTIVES

Epigenetic mechanisms regulate the structure, function and stability of chromatin, the physiological template of our genome. Breakdown of these mechanisms can unleash a host of catastrophic consequences for cells including deregulation of finely balanced gene transcription programs and DNA mutation, both of which are potent drivers of tumor initiation and progression. 

Our laboratory uses a range of biochemical, molecular and cellular biology approaches to uncover epigenetic mechanisms regulating normal cell physiology and tumorigenesis. A particular interest is to identify and characterize novel epigenetic complexes, molecular machines containing the enzymes and binding factors that alter chromatin structure and create alternate epigenetic states. The eventual goal of these studies is to devise new epigenetic approaches for improved cancer treatment. 

PROJECT

Epigenetics refers to the ability of cells and organisms to create, store and inherit new phenotypes without underlying changes to the genotype. The mechanisms encoding epigenetic information remain unclear, but to a large extent depend on regulating the structure and function of chromatin, a complex of genomic DNA and histone proteins. Chromatin is built around the repeating unit of the nucleosome, 146 bp of DNA wrapped 1.67 times around an octamer of histone proteins, and can form higher-order structures that regulate the associated DNA. Whereas compacted chromatin fibers, rich in internucleosomal contacts, are generally inhibitory to gene transcription, open structures with few internucleosomal contacts tend to be permissive. Factors that control the formation, stability and interchange of such chromatin states are thus poised to regulate gene expression and downstream phenotypes, and are candidate epigenetic factors.  These comprise a diverse array of chromatin modifying enzymes, binding proteins, non-coding RNAs and other molecules that typically assemble into a smaller number of large multi-functional complexes. Ongoing work in the laboratory is aimed at purifying and characterizing such epigenetic complexes, uncovering cellular and cancer pathways they regulate and understanding the underlying epigenetic mechanisms.


 Model of epigenetic regulation of physiologic and cancer mechanisms by SIRT1 complexes. SIRT1 promotes chromatin compaction and gene repression by erasing epigenetic marks associated with open chromatin structures and active gene transcription, including nucleosomal histone acetyl-lysine residues H3K9Ac, H4K16Ac and linker histone residue H1.4K26Ac. These marks are made by histone acetyltransferase (HAT) complexes upon recruitment to specific genomic loci, typically by transcription factors. The catalytic mechanism of SIRT1 requires the metabolic cofactor NAD+, and is sensitive to changes in its levels. In addition to deacetylated lysine residues, SIRT1 produces the metabolites nicotinamide (NAM), which is an inhibitor of SIRT1 activity, and O-acetyl-ADP-Ribose (O-AADPR), which may associate promote chromatin compaction. Interaction with binding partners and complexes targets SIRT1 activity to specific genomic loci, enabling regulation of discrete subsets of target genes. In this way, SIRT1 binding partners and complexes enable SIRT1 regulation of specific cellular, biological and disease processes.  However, few such SIRT1 complexes have been identified. DNA damage and loss of genome integrity, which can drive tumor initiation and progression, are also observed upon either loss or gain of SIRT1 function, but the mechanisms remain unclear.


Current studies are focused on the Class III NAD+ dependent histone deacetylase (HDAC) SIRT1, an enigmatic epigenetic factor that promotes chromatin compaction and gene repression. A particular importance of SIRT1 in regulation of chromatin compaction is implied by its specialized role as a deacetylase of histone H4 lysine 16 (H4K16), acetylation of which is sufficient to prevent higher order chromatin compaction. SIRT1 also regulates a broad spectrum of cellular and cancer processes - including genome stability, energy metabolism, apoptosis, necrosis, cell growth, angiogenesis and metastasis - and has been implicated in cancer as both tumor promoter and suppressor, in different contexts. We wish to understand how this single epigenetic factor regulates such diverse processes in normal and cancer cells. The intriguing metabolic regulation of SIRT1 by fluctuating NAD+ levels and other factors is also a research interest, especially its ability to act as a sensor of abnormal cancer cell metabolism. Altered tumor metabolism by mechanisms including the Warburg effect is an emerging hallmark of cancer, but its impact on epigenetic regulation is unclear. Collectively, these studies will guide preclinical evaluation of SIRT1 as a drug target and development of new epigenetic therapies for cancer.

The laboratory uses a range of biochemical, molecular biology and cell biology approaches to address these questions including mass spectrometry and next generation sequencing. We also have access to a range of core facilities including cancer specimen banks, tumor microdissection and high-throughput molecular analysis (DNA/RNA/protein), imaging facilities, a murine tumor model facility and a center for high-throughput drug screening and development, among others.

Positions are currently available for talented and highly motivated postdocs and students interested in working on these and related projects. To apply or enquire, send a CV and cover letter including a statement of your research interests and career goals to: peter.mulligan@lyon.unicancer.fr

PUBLICATIONS

1. Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, Martinez P, Keller PJ, Glover E, Richardson AL, Cowan J, Toland AE, Ravichandran K, Riethman H, Naber SP, Naar AM, Blasco MA, Hinds PW, Kuperwasser C. (2015). Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nature Communications, 6, Article number: 7505.

2. Toiber D, Erdel F, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa1, Agustina D’Urso S, Naar AM, Rippe K, and Mostoslavsky R. (2013). SIRT6 recruits SNF2h to sites of DNA breaks, modulating genomic stability through chromatin remodeling. Molecular Cell. Aug 22;51(4):454-68; Epub 2013 Jul 31.

3. Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, Wang Q, Kulkarni M, Najafi-Shoushtari SN, Mostoslavsky R, Gygi SP, Gill G, Dyson NJ and Näär AM. (2011). A SIRT1-LSD1 co-repressor complex regulates Notch target gene expression and development. Molecular Cell. Jun 10;42(5):689-99. Epub 2011 May 19.
 * Selected for Preview, Molecular Cell. Jun 10 (2011);42(5): 559-560

4. Di Stefano L, Walker JA, Burgio G, Corona D, Mulligan P, Näär AM and Dyson NJ. (2011). Functional antagonism between histone H3K4 demethylases in vivo. Genes and Development. Jan 1;25(1):17-28.

5. Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, Israelian K, Westphal CH, Rodgers JT, Shioda T, Elson SL, Mulligan P, Najafi-Shoushtari H, Black JC, et al. (2010). Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes and Development. Jul 1;24(13):1403-17.

6. Mulligan P, Westbrook TF, Ottinger M, Chang B, Pavlova NN, Macia E, Shi Y, Barretina J, Liu J, Howley PM, Elledge SJ and Shi Y. (2008). CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation. Molecular Cell. Dec 5;32(5):718-26.
 * Selected for Research Highlight, Nature Reviews Cancer. Feb (2009);9: 80; Leading Edge, Cell, Vol 135 (2008), p981.

7. Westbrook TF, Hu G*, Ang XL*, Mulligan P*, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ. (2008). SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature. Mar 20;452(7185):370-4.       *denotes equal contribution.

8.Wu S, Shi Y, Mulligan P, Gay F, Landry J, Liu H, Lu J, Qi HH, Wang W, Nickoloff JA, Wu C, Shi Y. (2007).  A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nature Structural and Molecular Biology.  Dec;14(12):1165-72.

9. Mulligan P, White NR, Monteleone G, Wang P, Wilson JW, Ohtsuka Y, Sanderson IR. (2006). Breast milk lactoferrin regulates gene expression by binding bacterial DNA CpG motifs but not genomic DNA promoters in model intestinal cells. Pediatric Research. 2006 May;59(5):656-61.

10.White NR, Mulligan P, King PJ, Sanderson IR. (2006). Sodium butyrate-mediated Sp3 acetylation represses human insulin-like growth factor binding protein-3 expression in intestinal epithelial cells. Journal of Pediatric Gastroenterology and Nutrition. Feb;42(2):134-41.

11.Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. Dec 29;119(7):941-53.

12. Mazzarella G, MacDonald TT, Salvati VM, Mulligan P, Pasquale L, Stefanile R, Lionetti P, Auricchio S, Pallone F, Troncone R, Monteleone G. (2003). Constitutive activation of the signal transducer and activator of transcription pathway in celiac disease lesions. American Journal of Pathology. Jun;162(6):1845-55.

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