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Dr. Karim Bouazoune Team 

We are interested in understanding how chromatin/epigenetic factors regulate genome functions, at the molecular level. In addition, we investigate how mutation of these factors contribute to human diseases. More specifically, we focus on molecular motors called chromatin or nucleosome remodeling factors. These enzymes use ATP hydrolysis to translocate onto DNA and change DNA accessibility by moving along histone proteins (which pack the DNA into nucleosomes). The functional importance of these enzymes is well-illustrated by the fact that their mutation causes, or is associated with, many human developmental disorders and cancer. For instance, we mainly focus on CHD7 which is mutated in CHARGE syndrome, Idiopathic Hypogonadotropic Hypogonadism, Kallmann Syndrome, Autism Spectrum Disorders, DiGeorge Syndrome and nonsyndromic patients with congenital heart defects (Yan S. et al., Proc Natl Acad Sci U S A. 2020 and refs. therein). It is therefore important to understand how CHD7 regulates genome functions and how mutations of CHD7 impact these functions. To answer these questions, we predominantly use biochemical approaches. In addition to further expanding our basic knowledge of chromatin remodeling enzymes, our goal is also to identify strategies to treat, and why not cure, pathologies resulting from mutation of these enzymes.

 

Joanna Brühl’s project: 

Acute myeloid leukemia (AML) is the most common type of aggressive blood cancer in adults and this pathology has an overall 5-year survival rate of about 25%. Treatment of most AML patients often involves the use of two chemotherapeutic drugs, cytarabine (ara-C) and an anthracycline-family drug such as daunorubicin (DNR), both of which lead to DNA damages. In addition, histamine (plus interleukin-2) or agents which interfere with DNA methylation such as aza-cytidine have been shown to provide reproducible but modest improvements (Voso MT et al., Curr Opin Oncol. 2015). Therefore, there is a strong need for identifying novel therapeutic targets to develop alternative or synergistic therapies to treat AML patients. Over the last decade or so, the development of drugs interfering with cellular epigenetic landscapes has been recognized as a promising approach to control cancer cell proliferation. Thus, in this project, we aim to identify epigenetic regulators that can potentially serve as novel targets for therapies in AML.

Publications

Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
Kargapolova, R. Rehimi, H. Kayserili, J. Brühl, K. Sofiadis, A. Zirkel, S. Palikyras, A. Mizi, Y. Li, G. Yigit, A. Hoischen, S. Frank, N. Russ, J. Trautwein, B. van Bon, C. Gilissen, M. Laugsch, E. G. Gusmao, N. Josipovic, J. Altmüller, P. Nürnberg, G. Längst, F. J. Kaiser, E. Watrin, H. Brunner, A. Rada-Iglesias, L. Kurian, B. Wollnik, K. Bouazoune* & A. Papantonis*. (Nat Commun. 2021. In press)

 

CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.
Yan S, Thienthanasit R, Chen D, Engelen E, Brühl J, Crossman DK, Kesterson R, Wang Q, Bouazoune K*, Jiao K*. Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28847-28858

The DNA repair protein SHPRH is a nucleosome-stimulated ATPase and a nucleosome-E3 ubiquitin ligase.
Brühl J, Trautwein J, Schäfer A, Linne U, Bouazoune K. Epigenetics Chromatin. 2019 Aug 21;12(1):52.

ortho-Fluoroazobenzene derivatives as DNA intercalators for photocontrol of DNA and nucleosome binding by visible light.
Heinrich B, Bouazoune K, Wojcik M, Bakowsky U, Vázquez O. Org Biomol Chem. 2019 Feb 13;17(7):1827-1833.

EcR recruits dMi-2 and increases efficiency of dMi-2-mediated remodelling to constrain transcription of hormone-regulated genes.
Kreher J, Kovač K, Bouazoune K, Mačinković I, Ernst AL, Engelen E, Pahl R, Finkernagel F, Murawska M, Ullah I, Brehm A. Nat Commun. 2017 Apr 5;8:14806.

Assembly, remodelled.
Bouazoune K, Kingston RE. Elife. 2013 Aug 20;2:e01270.

SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling.
Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa S, D'Urso A, Näär AM, Kingston R, Rippe K, Mostoslavsky R. Mol Cell. 2013 Aug 22;51(4):454-68.

Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders.
Bouazoune K, Kingston RE. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19238-43.

Methylation-sensitive single-molecule analysis of chromatin structure.
Miranda TB, Kelly TK, Bouazoune K, Jones PA. Curr Protoc Mol Biol. 2010 Jan;Chapter 21:Unit 21.17.1-16.

Analysis of individual remodeled nucleosomes reveals decreased histone-DNA contacts created by hSWI/SNF.
Bouazoune K, Miranda TB, Jones PA, Kingston RE. Nucleic Acids Res. 2009 Sep;37(16):5279-94.

ATP-dependent chromatin remodeling complexes in Drosophila.
Bouazoune K, Brehm A. Chromosome Res. 2006;14(4):433-49. Review.

dMi-2 chromatin binding and remodeling activities are regulated by dCK2 phosphorylation.
Bouazoune K, Brehm A. J Biol Chem. 2005 Dec 23;280(51):41912-20.

The dosage-compensation complex in flies and humans.
Bouazoune K, Korenjak M, Brehm A.
Genome Biol. 2004;5(11):352.

The dMi-2 chromodomains are DNA binding modules important for ATP-dependent nucleosome mobilization.
Bouazoune K, Mitterweger A, Längst G, Imhof A, Akhtar A, Becker PB, Brehm A. EMBO J. 2002 May 15;21(10):2430-40.