Epigenetic regulation of chromatin function
Co-workers: Dr Neil Blackledge, Dr Emilia Dimitrova, Dr Vincenzo Di Cerbo, Dr Angelika Feldmann, Mr Hamish King, Ms Anne Turberfield, and Ms Nadezda Fursova
Virtually every cell in the body has the same genetic information yet individual cells can achieve highly specialized states with vastly differing morphology and functionality. During development this is achieved through a series of cell expansion and differentiation cascades that allows initially pluripotent cells to commit to altered cells fates in a remarkably stable manner. Given that these outcomes are achieved with a fixed genetic complement (i.e. the same DNA in every cell), it reasons specific cell types must invoke with high fidelity mechanisms that specify and restrict their capacity to express the correct complement of genes.
It is clear that transcription factors which recognise specific DNA sequences in gene regulatory elements play a central role in defining gene expression outcome. However the vertebrate genome is vast, containing all the coding and structural information required to make gene products and effectively segregate chromosomes following cell division. Therefore only a small percentage of the total genome sequence is utilized to directly specify whether genes should be expressed or not. Recognizing this small fraction of the genome represents a formidable task for the gene expression machinery. This is complicated by the fact that DNA is not simply found as naked template but is instead wrapped into a structural entity called chromatin that consists of both DNA and protein encoded histone molecules. Recently it has become clear that gene regulatory elements in vertebrate genomes have a very specific chromatin modification architecture that differs from surrounding non-regulatory regions of the genome. Importantly this chromatin architecture can be specific to individual cell types, suggesting that this may play an important role in allowing individual cell types to achieve defined gene expression outcomes.
In understanding how chromatin and epigenetics contributes to gene regulation, the Klose lab has discovered that a ZF-CxxC DNA binding domain can recognize an epigenetically distinct state of DNA at gene regulatory elements called CpG islands. This DNA binding domain recruits a further set of chromatin modifying enzymes that alter the post-translational state of histone molecules in chromatin. This fundamental discovery places ZF-CxxC domain containing proteins as central players in chromatin modification at the majority of genes throughout the genome.
Building on this discovery the Lab is now focussed on understanding three central questions related to how this interesting system works to regulate gene expression:
- How do the family of ZF-CxxC domain containing proteins recognize and modify chromatin at gene regulatory elements?
- What does the chromatin architecture at gene promoters contribute to gene regulation?
- Why do CpG islands remain free of DNA methylation when the majority of the genome is densely methylated?
Our motivation for understanding these fundamental questions about gene regulation is to ultimately inform therapeutic approaches to counteract these processes when they malfunction in cancer and other human diseases.
Watch Prof. Klose presenting his work on 'Gene Regulation and the Epigenome' during his Royal Society Francis Crick Lecture.
Blackledge NP, Farcas AM, Kondo T, King H, McGouran JF, Hanssen LLP, Ito S, Cooper S, Kondo K, Koseki Y, Ishikura T, Long HK, Sheahan TW, Brockdorff N, Kessler BM, Koseki H, Klose RJ. Variant PRC1 complex dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell, 2014.
Long HK, Sims D, Heger A, Blackledge NP, Kutter C, Wright ML, Grützner F, Odom DT, Patient R, Ponting CP, Klose RJ. Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates. Elife. 2013
Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR, Lee S, Sims D, Cerase A, Sheahan TW, Koseki H, Brockdorff N, Ponting CP, Kessler BM, Klose RJ. KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. Elife. 2012
Zhou JC, Blackledge NP, Farcas AM, Klose RJ. Recognition of CpG island chromatin by KDM2A requires direct and specific interaction with linker DNA. Molecular and Cellular Biology. 2012
- Blackledge NP, Zhou JC, Tolstorukov MY, Farcas AM, Park PJ, Klose RJ. CpG Islands Recruit a Histone H3 Lysine 36 Demethylase. Molecular Cell. April, 2010
Figure 1 - (A) KDM2A utilises a ZF-CxxC domain to bind non-methylated DNA. (B) ChIP-seq analysis of KDM2A binding genome-wide reveals a specific nucleation this enzyme at CpG island elements. (C) KDM2A is targeted to non-methylated regions of the genome in vivo
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