MRC Career Development Fellow / Lecturer
Summary of Research
Chromatin conformation in transcriptional regulation
It has been known for a long time that chromatin is organised in a non-random manner in the nucleus, however only recently has it become possible to assay the fine structure of chromatin in an unbiased genome-wide manner using the Hi-C technique and its derivatives. Hi-C is a sequencing-based method to assess the 3D structure of the chromatin. It takes a snapshot of the chromatin architecture by crosslinking DNA with proteins, which hold together distant DNA regions, and after digesting the genome with a restriction enzyme, interacting DNA regions are ligated together and sequenced by paired-end sequencing. This allows for identification of both structural and functional chromatin interactions and further analysis of these can reveal how the 3D folding of the genome influences gene expression.
There are 3 main questions that are addressed in the lab:
- How can we exploit chromatin structure information for understanding the effect of GWAS loci?
- How chromatin interactions change during development?
- What are the important regulatory interactions in diseases such as leukaemia?
Figure 1. Use of promoter capture Hi-C in GWAS annotation. A) Schematic of the promoter capture Hi-C protocol and a representative result for one promoter. B) GWAS lead SNPs that are associated with diseases/traits relevant for the cell type are enriched in the promoter interacting regions. (adapted from Mifsud et al. 2015)
Cresswell, GD; Apps, JR; Chagtai, T; Mifsud, B; Bentley, CC; Maschietto, M; Popov, SD; Weeks, ME; Olsen, ØE; Sebire, NJ; Pritchard-Jones, K; Luscombe, NM; Williams, RD and Mifsud, W.
Intra-tumor genetic heterogeneity in Wilms tumor: clonal evolution and clinical implications.
EBioMedicine. 2016 Jul;9:120-9
Schoenfelder S.*, Sugar R.*, Dimond A.*, Javierre B-M.*, Armstrong H.*, Mifsud B., Dimitrova E., Tavares-Cadete F., Furlan-Magaril M., Jurkowski W., Segonds-Pichon A., Wingett S., Tabbada K., Andrews S., Herman B., LeProust E., Osborne C.S., Koseki H., Fraser P., Luscombe N.M., Elderkin S.
Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome.
Nature Genetics. 2015 Oct;47(10):1179-86
Mifsud B.*, Tavares-Cadete F.*, Young A. N.*, Sugar R., Schoenfelder S., Ferreira L., Wingett S. , Andrews S., Grey W., Ewels P.A., Herman B., Happe S., Higgs A., LeProust E., Follows G.A., Fraser P., Luscombe N.M., Osborne C.S.
Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C.
Nature Genetics. 2015 Jun;47(6):598-606
Schoenfelder S.*, Furlan-Magaril M.*, Mifsud B.*, Tavares-Cadete F.*, Sugar R., Javierre B-M., Nagano T., Katsman Y., Sakthidevi M., Wingett S. W., Dimitrova E., Dimond A., Edelman L. B., Elderkin S., Tabbada K., Darbo E., Andrews S., Herman B., Higgs A., LeProust E., Osborne C.S., Mitchell J.A., Luscombe N.M., Fraser P.
The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements.
Genome Research. 2015 Apr;25(4):582-97
Bulut-Karslioglu A.*, de la Rosa-Velazquez I.A.*, Ramirez F., Barenboim M., Onishi-Seebacher M., Arand J., Galan C., Winter G.E., Engist B., Gerle B., O’Sullivan R.J., Martens J.H., Walter J., Manke T., Lachner M., Jenuwein T.
Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells.
Mol cell. 2014; 55(2):277-90
Bulut-Karslioglu A.*, Perrera V.*, Scaranaro M., de la Rosa-Velazquez I.A., van de Nobelen S., Shukeir N., Popow J., Gerle B., Opravil S., Pagani M., Meidhof S., Brabletz T., Manke T., Lachner M., Jenuwein T.
A transcription factor-based mechanism for mouse heterochromatin formation.
Nat Struct Mol Biol. 2013; 20(2):244