1. Transcription regulation in development
The Mueller group investigates transcriptional regulation processes that regulate protein coding and non-coding gene activities during and after the transition from a pluripotent cell mass of the blastula into a highly complex, differentiated vertebrate embryo. They combine comparative genomics and in vivo functional analysis of gene regulation exploiting the capabilities offered by the zebrafish model system. They have developed new techniques for high throughput in vivo analysis of cis-regulatory modules (CRMs) aiding in the identification of a large number of transcriptional enhancer elements in developmental genes. Their research contributed to the understanding of the complexity of promoter regulation by the characterisation of novel members of the TATA binding protein family and the functional characterisation of vertebrate promoter recognition proteins. They established novel in vivo assays of studying general transcription factors in the complexity of the embryo using embryo manipulation tools and modern genomics techniques (RNA, CAGE and ChIP sequencing). Lab members working on the topic: Dr Yavor Hadzhiev, Dr Nan Li, Dr Padma Putta, Ms Jennifer Roberts.
2. Zebrafish as a vertebrate model for human genetics / disease
i) Non-coding mutations in disease
CRMs and other non-coding functional elements of developmental regulator genes are mutated in numerous congenital disorders. The aberration of gene expression regulation can also lead to multifactorial diseases. The identification of non-coding functional elements will greatly enhance efforts in mapping non-coding mutations responsible for congenital and multifactorial disorders. Mueller and collaborators (U. Liebel and M. Reischl at KIT, Karlsruhe) pioneered the automation of imaging of tens of thousands of transgenic zebrafish embryos in order to initiate high throughput screens for mutation carrying cis-regulatory elements. To complement the technology development they apply bioinformatics (comparative genomics) and biochemical prediction of cis-regulatory modules (ChIP sequencing). They collaborate with B. Lenhard (Uni Bergen) E. Stupka (UCL), P. Carninci (RIKEN) and U. Straehle (KIT, Karlsruhe) in a concerted effort to map the functional CRMs of zebrafish. Ultimately, this work will aid in their effort to develop the transparent and fast developing fish embryo as a high throughput transgenic sensor for efficient screening of functionally conserved cis-regulatory elements relevant in human diseases. Lab members working on the topic: Dr Yavor Hadzhiev, Ms Irene Miguel.
ii) Zebrafish models for genetic disorders
The Mueller group utilises their functional genomic experience with the fish model and collaborate with clinical and non-clinical investigators in their search for the in vivo function of disease causing genes. In the last 3 years they made progress by establishing a new zebrafish model for the Birt-Hogg-Dube syndrome (with E. Maher). They have been studying the biological function of genes with newly discovered disease causing mutations and demonstrated essential organogenesis functions for genes causing familial syndromes such as ARC and Warburg Micro syndromes (collaborations with E. Maher, P. Gissen, I. Alianidis). Lab members working on the topic: Dr Emma Kenyon, Dr Nan Li, Harmeet Gill.
iii) Phenotype detection for drug screening
Based on their experience with high throughput screening of zebrafish embryos, the Mueller group is exploiting automated imaging to screen gene expression phenotypes and develop novel methods for physiological phenotype detection to screen for drug effects in zebrafish embryos (collaboration with U. Liebel, Karlsruhe and A. Sik, Bham). Lab members working on the topic: Dr Yavor Hadzhiev, Mr Sundeep Dhillon.
Haberle V, Li N, Hadzhiev Y, Plessy C, Previti C, Nepal C, Gehrig J, Dong X, Akalin A, Suzuki A-M, van IJcken W, Armant O, Ferg M, Strähle U, Carninci P, Müller F* and Lenhard B (2014) Two independent transcription initiation codes overlap on vertebrate core promoters. Nature [Epub ahead of print] *co-corresponding author
Roberts JA, Miguel-Escalada I, Slovik KJ, Walsh KT, Hadzhiev Y, Sanges R, Stupka E, Balciuniene J, Marsh EK, Balciunas D and Müller F (2014) Targeted transgene integration overcomes variability of position effects in zebrafish. Development 141(3):715-24
Nepal C, Hadzhiev Y, Previti C, Haberle V, Li N, Takahashi H, Suzuki A-M S, Sheng Y, Abdelhamid RA, Anand S, Gehrig J, Akalin A, Kockx CEM, van der Sloot AAJ, van IJcken WFJ, Armant O, Rastegar S, Watson C, Strähle U, Stupka E, Carninci P, Lenhard B and Müller F (2013) Dynamic regulation of the transcription initiation landscape at single nucleotide resolution during vertebrate embryogenesis. Genome Research 23(11):1938-50
Pasquali L, Gaulton KJ, Rodríguez-Seguí S, Mularoni L, Miquel-Escalada I, Akerman I, Tena JJ, Morán I, Gomez-Marin C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, García-Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Skarmeta JL, Müller F, McCarthy M and Ferrer J (2014) Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nature Genetics 46(2):136-43
Lindeman LC, Andersen IS, Reiner AH, Li N, Aanes H, Ostrup O, Winata C, Mathavan S, Müller F, Aleström P and Collas P (2011) Prepatterning of Developmental Gene Expression by Modified Histones before Zygotic Genome Activation. Dev Cell 21(6):993-1004
Cullinane AR, Straatman-Iwanowska A, Zaucker A, Wakabayashi Y, Bruce CK, Luo G, Rahman F, Gürakan F, Utine E, Ozkan TB, Denecke J, Vukovic J, Di Rocco M, Mandel H, Cangul H, Matthews RP, Thomas SG, Rappoport JZ, Arias IM, Wolburg H, Knisely AS, Kelly DA, Müller F, Maher ER and Gissen P (2010) Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. Nat Genet 42(4):303-12
Gehrig J, Reischl M, Kalmar E, Ferg M, Hadzhiev Y, Zaucker A, Song C, Schindler S, Liebel U and Müller F (2009) Automated high throughput mapping of promoter-enhancer interactions in zebrafish embryos. Nature Methods 6(12):911-6
Ferg M, Sanges R, Gehrig J, Lovas A, Bauer M, Kiss J, Szabo M, Olasz F, Pankratz M, Stupka E and Müller F (2007) The TATA binding protein (TBP) regulates maternal mRNA degradation and differential zygotic gene activation in the zebrafish embryo. EMBO J 26(17):3945-56