Dr Mark Christian

Background

Our laboratory is focused on determining the mechanisms that regulate gene expression in development and metabolism. It is increasingly evident that epigenetic gene regulatory mechanisms have important roles in cell differentiation and the etiology human diseases. Epigenetic mechanisms include DNA methylation and the expression and action of microRNA genes. We are defining the action of hormones and dietary stimuli on epigenetic programming in early life. Programming factors include nutrients, hormones and environmental chemicals.
Determining the mechanisms that regulate 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. 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.
We are also investigating the ability of nuclear receptors and their coregulators to affect metabolic gene expression. This work has 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 will address questions relating to 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.

Aims

1) To elucidate the epigenetic mechanisms that mediate fetal programming.
2) To determine the roles of microRNAs in endometrial differentiation.
3) To identify the molecular mechanism of CIDEA-dependent lipid droplet induction and determine its action in vivo.

Research

1) Epigenetic programming events during early life

It is increasingly evident that epigenetic gene regulatory mechanisms have important roles in the etiology human diseases. Early life programming by exposure to elevated glucocorticoid levels or dietary PUFAs is likely to be mediated by epigenetic events. A significant mechanism for permanently determining gene expression is CpG methylation. By manipulation of maternal diet and hormone levels during gestation and lactation we will monitor changes in gene expression and epigenetic modifications in developing mice to correlate with metabolic disorders in adults. More specifically, we will use the viable agouti yellow (Avy) mouse to assess the influence of different stimuli on epigenetic programming. This strain contains a retroviral insertion in the promoter of the agouti gene that results in coat colour distribution being susceptible to the establishment of CpG methylation at the Avy metastable epiallele; hypermethylation results in brown colour and hypomethylation leads to yellow coat colour. This mouse model, effectively an epigenetic biosensor, has been utilised previously to determine the ability of maternal diets, supplemented with either genistein or methyl donors, to modulate CpG methylation and control offspring gene expression.
Over the last decades the ratio of n-6 to n-3 PUFAs in Western dietary intake has significantly increased. PUFAs of the n-6 series, as opposed to the n-3 series, are potent promoters of adipose tissue development in vivo during the gestation/lactation period. Because peroxisome proliferator-activated receptors (PPARs) are activated by fatty acids and are essential for adipocyte differentiation and function they represent likely targets for mediating the action of dietary fatty acids on fetal programming. Glucocorticoid exposure during gestation has been found to affect the metabolic phenotype resulting in hypertension, hyperglycaemia and insulin resistance in adulthood. The developing fetus is normally protected from maternal glucocorticoids by placental expression of the enzyme 11-Hydroxysteroid dehydrogenase type 2 (11-HSD2). This protective mechanism may be overcome by downregulation of the enzyme, elevated levels of endogenous maternal glucocorticoid levels, or administration of synthetic glucocorticoids. We will use the Avy mouse to study the programming action of elevated glucocorticoid levels or dietary changes in the n-6:n-3 PUFA ratio on CpG methylation.

2) The importance of microRNAs in endometrial differentiation

Determination of the mechanisms that regulate gene expression in reproductive tissues is key to our understanding of fertility and the identification of targets for contraception. 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. Decidual transformation of human endometrial stromal cells represents a process of morphological differentiation accompanied by distinct biochemical phenotypic changes. Identification of the mechanisms, present in decidualising cells, that determine the stability or translation of mRNA will help elucidate how the profound changes in the pattern of gene expression following differentiation are controlled. There is increasing evidence that miRNAs are involved in biological processes such as muscle proliferation and differentiation, brain morphogenesis, hematopoietic lineage differentiation. However, their role in reproductive tissues is still to be fully determined. This project will investigate the role of miRNAs in human endometrial cells and therefore increase our knowledge of the gene regulatory programmes required for fertility.

3) Lipid droplet induction due to CIDE proteins

The largest energy reserve in mammals is fat. Excessive fat storage and obesity results from an imbalance between energy intake and expenditure and is a major risk for many metabolic diseases, such as hypertension, stroke, liver steatosis, and even cancer. 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. Within the past year 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 will investigate the regulation and in vivo roles of CIDEA and the related proteins CIDEB and FSP27 in lipid accumulation.

Team members

Kunal Shah (BBSRC funded PhD student)
Evanthia Nikolopoulou (IOG trust funded Research Assistant)

Selected Publications

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. In Press.

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.

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):243-50.

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):9383-91.

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):5233-44.

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):8437-42.

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, 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 Jun 7;277(23):20825-32.

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 Jan;16(1):141-54.