Ph.d. student / Ph.d. studerende
Genomic regulatory landscapes and chromosomal rearrangements
The main objective of the PhD study is to search for, identify and characterize chromosomal rearrangements within putative regulatory landscapes around evolutionary conserved key developmental (trans-dev) genes.
It was recently discovered that not only does mutation of trans-dev genes cause disease, but so does disruption of the regulatory landscapes surrounding these genes, e.g. by translocations that remove regulatory elements from the gene they regulate. One example of this so called long-range position effect has been described in Campomelic dysplasia (CD), where chromosomal breakpoints located more than 1 Mb from SOX9 still cause CD, or a milder form. Similar long-range position effects have been associated with other diseases such as Rieger syndrome (PITX2) and Aniridia (PAX6).
A common theme for trans-dev genes is that they are associated with gene poor or empty regions, enriched for evolutionary conserved non-coding elements (CNE). Some of these CNEs have been shown to function as tissue-specific enhancers and the combined effect of these enhancers (and probably also other regulatory elements) are believed to determine the complex spatio-temporal expression of the associated trans-dev gene. Since these regulatory elements are cis-acting, balanced chromosomal rearrangements associated with abnormal phenotypes that do not truncate protein coding genes may potentially identify novel regulatory landscapes. Furthermore, the molecular mapping of the breakpoint involved may be used to link the associated phenotype with the position and tissue specificity of the individual CNEs.
In the PhD study I have studied several chromosomal rearrangements with breakpoints in the vicinity of trans-dev genes. This includes chromosomal rearrangements compatible with known phenotype/genotype associations (Rieger/PITX2; MR/AUTS2), and chromosomal rearrangements with breakpoints within putative regulatory landscapes of genes where human phenotypes are unknown (HMX2/HMX3, FOXP1 and POU4F2). The mapping of the breakpoints was supplemented with functional characterization of selected CNEs (HMX2/HMX3, FOXP1) by a zebrafish assay, in order to confirm the hypotheses that the expression of CNEs coincides with the endogenous expression of the gene they regulate.
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Publications related to WJC
|2.|| || Engenheiro E, Møller RS, Pinto M, Soares G, Nikanorova M, Carreira IM, Ullmann R, Tommerup N, Tümer Z. Mowat-Wilson syndrome: an underdiagnosed syndrome?. Clin Genet. 2008;73:579-84.|
|1.|| || Engenheiro E, Saraiva J, Carreira I, Ramos L, Ropers H, Silva E, Tommerup N, Tumer Z. Cytogenetically invisible microdeletions involving PITX2 in Rieger syndrome. Clin Genet. 2007;72:464-70.|
Presentations related to WJC
|11th International Congress of Human Genetics (ICHG 2006)|
Brisbane, August 06, 2006
|7.|| || Engenheiro E, Goode D, Callaway H, Pinto M, Soares G, Woolfe A, Tümer Z, Elgar G, Tommerup N. Disruption of a cluster of conserved non-coding elements by a translocation breakpoint distal to HMX2/HMX3. |
|NOK 2006 XXXVII Nordic Congress of Ophthalmology|
Copenhagen, Denmark - June 17-20, 2006, June 17, 2006
|6.|| || Hansen L, Rosenberg T, Thygesen J, Bek T, Kreiborg S, Engenheiro E, Tommerup N. The genetic background for Rieger syndrome, Rieger’s anomaly and Peters’ anomaly – a complex etiology with complex genetics. Acta Ophthalmologica Scandinavica, June 2006 - Vol. 84 Issue s238 Page 4-122.
|European Human Genetics Conference 2005 (ESHG 2005)|
Prague, May 07, 2005
|5.|| || Hjorth M, Engenheiro E, Holstebroe S, Bache I, Bugge M, Tumer Z, Tommerup N. Visualization of 2260 chromosomal breakpoints in Mendelian Cytogenetics Network database associated with Mental Retardation. |
|4.|| || Engenheiro E, Carvalho T, Marques I, Ramos L, Kalscheuer V, Tümer, Z Carmo-Fonseca M, Tommerup N. Reduced cajal body number in a patient haploinsufficient for COIL. |
|54th Meeting of the American Society of Human Genetics|
Toronto, Canada, October 25, 2004
|3.|| || Engenheiro E, Pinto M, Soares G, Marques I, Kalscheuer V, Tommerup N. A Complex Chromosomal Rearrangement associated with Mowat-Wilson Syndrome. |
|53rd Meeting of the American Society of Human Genetics|
Los Angeles, USA, November 03, 2003
|2.|| || Saraiva J, Engenheiro E, Tommerup N, Matoso E, Marques I. Rieger syndrome and a de novo (4;17)(q25; q23.3) translocation. The American Journal of Human Genetics.
|European Human Genetics Conference 2003|
Birmingham, England, May 02, 2003
|1.|| || Engenheiro E, Pinto M, Lima M R, Soares G, Marques I, Kalscheuer V, Tommerup N. A t(10;13)(q26;q31)de novo in a patient with mental retardation, epilepsy and ataxia. |
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