Julie Ahringer PhD FMedSci, Wellcome Senior Research Fellow, Member of the Genetics Department
The control of chromatin structure and function
Chromatin regulation plays a central role in transcriptional control and genome organisation, and also impacts mRNA post-transcriptional events. C elegans is an excellent system for studies of chromatin function due to its small well-annotated genome, powerful RNAi technology, and rich resource of chromatin mutants. We generated and analysed a genome-wide map of 18 histone modifications, finding that modifications are organised into broad domains that differently mark the central and distal regions and that genes are locally organised into active and inactive blocks. We also discovered specific modifications that mark exons and the X-chromosome, and that the latter is important for global downregulation of X-linked gene expression during dosage compensation. We are studying the functions of histone modifications in transcriptional and post-transcriptional processes.
It has recently been shown that RNA Polymerase II transcription is far more extensive than previously thought, much of it not associated with protein-coding genes. To investigate this phenomenon, we recently carried out the first global mapping of transcription initiation and elongation in C elegans. We found that transcription initiation is usually bidirectional and that the majority of initiation events occur in regions with enhancer-like chromatin signatures. These regions show a novel regulatory architecture, whereby upstream enhancers are transcribed towards and in the same orientation at that of the nearest downstream gene.
We also study the functions of C elegans counterparts of major chromatin regulatory complexes implicated in human disease, including the histone deacetylase complex NuRD, the Retinoblastoma complex DRM, and a TIP60 histone acetyltransferase complex. We investigate the function of these proteins in transcriptional control and development using chromatin immunoprecipitation followed by deep sequencing, global mRNA expression analyses and other genetic and genomic methods.
We recently completed 17 systematic genetic interaction RNAi screens for cell polarity genes. In the resulting functional map of 184 genes, 72% were not previously linked to cell polarity and 80% have human homologs. This network should be widely applicable across animals given the conservation known cell polarity mechanisms.
• Chen RA-J, Down TA, Stempor P, Chen QB, Egelhofer TA, Hillier LW, Jeffers TE and Ahringer J (2013) The landscape of RNA polymerase II transcription initiation in C. elegans reveals enhancer and promoter architectures, Genome Research 8, 1339-47
• Fievet BT*, Rodriguez J*, Naganathan S, Lee C, Zeiser E, Ishidate,T, Shirayama M, Grill S and Ahringer J (2012) Systematic genetic interaction screens uncover cell polarity regulators and functional redundancy. Nature Cell Biology 15 (1), 103-112
• Vielle A, Lang J, Dong Y, Ercan S, Kotwaliwale C, Rechtsteiner A, Appert A, Chen QB, Dose A, Egelhofer T, Stempor P, Dernburg A, Lieb J, Strome S and Ahringer J (2012) H4K20me1 contributes to downregulation of X-linked genes for C. elegans dosage compensation. PLoS Genetics (9): e1002933
• Kolasinska-Zwierz P, Down T, Latorre I, Liu T, Liu XS and Ahringer J (2009) Differential chromatin marking of introns and expressed exons by H3K36me3. Nature Genetics 41, 376-381
• Gerstein MB, modENCODE Consortium, Ahringer J, Strome S, Gunsalus KC, Micklem G, Liu XS, Reinke V, Kim SK, Hillier LW, Henikoff S, Piano F, Snyder M, Stein L, Lieb JD, Waterston RH. (2010) Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project. Science 330, 1775-87.