Dr Mark Christian
Our laboratory is focused on determining the mechanisms that regulate gene expression in development and metabolism. We are characterising cells of the anatomically distinct white and brown adipose tissue depots and defining the action of hormones and dietary stimuli on adipocyte biology.
WAT and BAT
Energy homeostasis is crucial since excess fat storage leads to obesity and negatively impacts the body’s metabolic health with associated predisposition to diseases including diabetes. There are two distinct types of adipose tissue: 1) White adipose tissue (WAT) is considered to negatively impact on health due to its role in triglyceride storage and associated obesity. 2) Brown adipose tissue (BAT), in contrast, is considered to be favourable to health. Exposure to the cold rapidly activates signalling pathway in BAT which modulate gene expression and promote the capacity for thermogenesis and consumption of fat stores. Remarkably, WAT depots can also respond to a long term cold stimulus by specific genetic and morphological changes that result in a more BAT-like appearance. These changes could arise due to specific development from stem cells or preadipocytes in the WAT depot or transdifferentiation of fully mature adipocytes.
CIDE and Lipid Droplets
Investigating the ability of nuclear receptors and their coregulators to affect metabolic gene expression led us to the study of the biological roles of the CIDE (Cell Death-Inducing DFF45-like Effector) family of genes in lipid droplet induction and the control of energy metabolism in metabolic cells. By studying the function and regulation of this family of proteins, we are determining the impact of CIDE proteins on lipid storage in different metabolic tissues, the importance of controlling the expression of metabolic regulatory systems in response to environmental stimuli, and the impact of tissue-specific gene expression on whole body metabolic function and in metabolic disease.
MicroRNAs and Decidualization
MicroRNAs are important regulators of gene expression and essential for cell differentiation. Determination of the mechanisms that control gene expression in cycling endometrium is key to our understanding of normal fertility and pathological conditions, such as infertility, recurrent pregnancy loss, and a spectrum of obstetrical disorders associated impaired deep placentation, such as fetal growth restriction and preeclampsia.
1) To identify the molecular mechanism of CIDEA-dependent lipid droplet induction and determine its action in vivo.
2) To determine the factors that control the switch between white and brown adipose tissue.
3) To determine the role of fatty acids in adipocyte differentiation.
4) To determine the roles of microRNAs in endometrial differentiation.
1) Lipid droplet induction due to CIDE proteins
The study of factors that control lipid storage in different tissues is essential for understanding and controlling metabolic disorders. Cellular lipid storage is determined by a group of proteins that coat lipid droplets and facilitate storage or utilisation by regulation of metabolic processes. In mammalian cells, these lipid-coating proteins are members of the PAT (perilipin-ADRP-TIP47) domain family, which include perilipin, ADRP (or adipophilin), TIP47, S3-12 and MLDP/OXPAT. Recently, additional proteins, including CIDEA by our own investigations, have been discovered to have important roles in lipid droplet formation and function. We found that CIDEA can induce lipid droplets in non-adipocyte cells and is localized on the surface of these organelles. We are investigating the regulation and in vivo roles of CIDEA and the related proteins CIDEB and FSP27 in lipid accumulation.
2) Characterising the temperature dependent switch from white to brown adipocytes
Defining the genes that promote brown fat induction, transdifferentiation and activation of the energy expenditure program will provide new applications for combating the obesity epidemic. We aim to (i) determine the factors and pathways that define the switch from WAT to BAT-like adipocytes following cold exposure and (ii) identify the genes and pathways that discriminate WAT and BAT depots. As visceral WAT is considered significantly more detrimental to metabolic health in comparison to subcutaneous WAT (iii) we are also characterizing the pathways and genes that discriminate these two white fat depots.
3) The role of fatty acids in adipocyte differentiation
Dietary fat has been correlated with obesity since it induces the proliferation and differentiation of pre-adipocytes. However it has become clear that the effect of fat on human health depends on the composition and the nature of fatty acids. Arachidonic acid is a major omega-6 polyunsaturated fatty acid with a controversial role in adipocyte differentiation. Using 3T3-L1 cells, we are investigating the effect of arachidonic acid exposure on pre-adipocyte differentiation. We are monitoring the gene expression events instigated by treatment with the fatty acid and defining the transcription factors and signal transduction pathways that modulate the differentation program.
4) The importance of microRNAs in endometrial differentiation
MicroRNAs (miRNAs) are genomically encoded, small, non-coding RNAs that regulate gene expression by controlling translation or stability of mRNAs. There are greater than 400 miRNAs identified, many of which display tissue specific expression patterns. They are key components in the regulation of developmental events and are required for cell fate specification and differentiation. During the menstrual cycle, ovarian estradiol and progesterone stimulate the ordered growth and differentiation of endometrial tissue compartments. We are studying microRNAs and their target genes involved in decidualization of human endometrium, defining their roles in regulating decidual cell function and examining if aberrant microRNA expression is associated with reproductive failure.
David Barneda-Ciurana (BBSRC funded Post Doctoral Researcher)
Meritxell Rosell-Mane (Wellcome Trust funded Post Doctoral Researcher)
Kunal Shah (BBSRC funded PhD student)
Evanthia Nikolopoulou (Genesis Research Trust funded PhD student)
Anthony Okolo (Delta State University funded PhD student)
Prof Jan J Brosens (University of Warwick)
Prof Saverio Cinti (University of Ancona)
Dr Ros John (Cardiff University)
Prof Dominic Withers (Imperial College London)
Prof James Scott (Imperial College London)
Dr Nicholas T Ktistakis (Babraham Institute)
Dr Giovanni Montana (Imperial College London)
Dr Raffa Carzaniga (Imperial College London)
Salker M, Christian M, Steel JH, Nautiyal J, Lavery S, Trew G, Webster Z, Al-Sabbagh M, Puchchakayala G, Föller M, Landles C, Sharkey AM, Quenby S, Aplin JD, Regan L, Lang F, Brosens JJ. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat Med. In Press.
Grimaldi G, Christian M, Steel JH, Henriet P, Poutanen M, Brosens JJ. Down-Regulation of the Histone Methyltransferase EZH2 Contributes to the Epigenetic Programming of Decidualizing Human Endometrial Stromal Cells. Mol Endocrinol. 2011 Sep 8. [Epub ahead of print]
Cloke B, Christian M. The role of androgens and the androgen receptor in cycling endometrium. Mol Cell Endocrinol. 2011 Jul 2. [Epub ahead of print]
Poliandri AH, Gamsby JJ, Christian M, Spinella MJ, Loros JJ, Dunlap JC, Parker MG. Modulation of Clock Gene Expression by the Transcriptional Coregulator Receptor Interacting Protein 140 (RIP140). J Biol Rhythms. 2011 26(3):187-199.
Christian M, Lam EW, Wilson MS, and Brosens JJ. FOXO transcription factors and their role in disorders of the female reproductive tract. Curr Drug Targets. 2011 12(9):1291-1302.
Al-Sabbagh M, Fusi L, Higham J, Lee Y, Lei K, Hanyaloglu AC, Lam EW, Christian M, Brosens JJ. NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling. Endocrinology. 2010 152(2):730-740.
Fritah A, Christian M, and Parker MG. The metabolic coregulator RIP140: An update. Am J Physiol Endocrinol Metab. 2010 299(3):E335-340.
Cloke B, Shah K, Kaneda H, Lavery S, Trew G, Fusi L, Higham J, Dina RE, Ghaem-Maghami S, Ellis P, Brosens JJ, Christian M. The Poly(C)-Binding Protein-1 Regulates Expression of the Androgen Receptor. Endocrinology. 2010 151(8):3954-64.
Christian M, Parker MG. The engineering of brown fat. J Mol Cell Biol. 2010 2(1):23-25.
Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, Dina RE, Brosens JJ, Ghaem-Maghami S, Lam EW. Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 2010 70(1):367-377.
Leitao B, Jones MC, Fusi L, Higham J, Lee Y, Takano M, Goto T, Christian M, Lam EW, Brosens JJ. Silencing of the JNK pathway maintains progesterone receptor activity in decidualizing human endometrial stromal cells exposed to oxidative stress signals. FASEB J. 2010 24(5):1541-1551.
Hallberg M, Morganstein DL, Kiskinis E, Shah K, Kralli A, Dilworth SM, White R, Parker MG, Christian M. A functional interaction between RIP140 and PGC-1 regulates the expression of the lipid droplet protein CIDEA. Mol Cell Biol. 2008. 28(22):6785-6798.
Zschiedrich I, Hardeland U, Krones-Herzig A, Berriel Diaz M, Vegiopoulos A, Müggenburg J, Sombroek D, Hofmann TG, Zawatzky R, Yu X, Gretz N, Christian M, White R, Parker MG, Herzig S. Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine gene expression. Blood. 2008 112(2):264-276.
White R, Morganstein D, Christian M, Seth A, Herzog B, Parker MG. Role of RIP140 in metabolic tissues: connections to disease. FEBS Lett. 2008 582(1):39-45.
Morganstein DL, Christian M, Turner JJ, Parker MG, White R. Conditionally immortalized white preadipocytes: a novel adipocyte model. J Lipid Res. 2008 49(3):679-685.
Kiskinis E, Hallberg M, Christian M, Olofsson M, Dilworth SM, White R, Parker MG. RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes. EMBO J. 2007 26(23):4831-4840.
Debevec D, Christian M, Morganstein D, Seth A, Parker M, White R. RIP140 regulates expression of Uncoupling Protein 1 in adipocytes through specific PPAR isoforms and ERR. Mol Endocrinol. 2007. 21(7):1581-1592.
Lopez-Garcia J, Periyasamy M,Thomas R, Christian M, Leao M, Jat P, Kindle KB, Heery DM, Parker MG, Buluwela L, Kamalati T, Ali S. ZNF366 is a Novel Corepressor that Regulates Estrogen Receptor Activity Through CtBP and HDAC Recruitment. Nucleic Acids Res. 2006. 34 (21): 6126-6136.
Nichol D, Christian M, Steel JH, White R, Parker MG. RIP140 expression is stimulated by ERR during adipogenesis. J. Biol. Chem. 2006. 281(43): 32140-32146.
Christian M, White R, Parker MG. Metabolic regulation by the nuclear receptor corepressor RIP140. Trends Endocrinol Metab. 2006. 17(6):243-250.
Schneider-Merck T, Pohnke Y, Kempf R, Christian M, Brosens JJ, and Gellersen B. Physical Interaction and Mutual Transrepression between CCAAT/Enhancer-binding Protein and the p53 Tumor Suppressor. J. Biol. Chem. 2006. 281: 269-278.
Christian M, Kiskinis E, Debevec D, Leonardsson G, White R, Parker MG. RIP140-targeted repression of gene expression in adipocytes. Mol Cell Biol. 2005. 25(21):9383-9391.
Pohnke Y, Schneider-Merck T, Fahnenstich J, Kempf R, Christian M, Milde-Langosch K, Brosens JJ, Gellersen. Wild-Type p53 Protein Is Up-Regulated upon Cyclic Adenosine Monophosphate-Induced Differentiation of Human Endometrial Stromal Cells. J Clin Endocrinol Metab. 2004 89(10):5233-5244.
Leonardsson G, Steel J, Christian M, Pocock V, Milligan S, Bell J, So PW, Gomez GM, Vidal-Puig A, White R, Parker M. The Nuclear Receptor Corepressor RIP140 Regulates Fat Accumulation. Proc Natl Acad Sci USA. 2004 101(22):8437-8442.
Zoumpoulidou G, Jones MC, de Mattos SF, Francis JM, Fusi L, Lee YS, Christian M, Varshochi R, Lam EW, Brosens JJ. Convergence of interferon-gamma and progesterone signaling pathways in human endometrium: role of PIASy (protein inhibitor of activated signal transducer and activator of transcription-y). Mol Endocrinol. 2004 18(8):1988-1999.
Christian M, Tullet JM, Parker MG. Characterisation of four autonomous repression domains in the corepressor RIP140. J Biol Chem. 2004 279(15):15645-15651.
Christian M, Mak I, White JO, Brosens JJ. Mechanisms of decidualization. Reprod Biomed Online. 2002;4 Suppl 3:24-30.
Dheenadayalu K, Mak I, Gordts S, Campo R, Higham J, Puttemans P, White J, Christian M, Fusi L, Brosens J. Aromatase P450 messenger RNA expression in eutopic endometrium is not a specific marker for pelvic endometriosis. Fertil Steril. 2002 78(4):825-9.
Mak IY, Brosens JJ, Christian M, Hills FA, Chamley L, Regan L, White JO. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J Clin Endocrinol Metab. 2002 87(6):2581-2588.
Christian M, Zhang X, Schneider-Merck T, Unterman TG, Gellersen B, White JO, Brosens JJ. Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein beta in differentiating human endometrial stromal cells. J Biol Chem. 2002 277(23):20825-20832.
Christian M, Pohnke Y, Kempf R, Gellersen B, Brosens JJ. Functional association of PR and CCAAT/enhancer-binding protein beta isoforms: promoter-dependent cooperation between PR-B and liver-enriched inhibitory protein, or liver-enriched activatory protein and PR-A in human endometrial stromal cells. Mol Endocrinol. 2002 16(1):141-154.
Christian M, Marangos P, Mak I, McVey J, Barker F, White J, Brosens JJ. Interferon-gamma modulates prolactin and tissue factor expression in differentiating human endometrial stromal cells. Endocrinology. 2001 142(7):3142-3151.
Christian M, Gillies G. Developing hypothalamic dopaminergic neurones as potential targets for environmental estrogens. J Endocrinol. 1999 160(3):R1-6.