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Adrian Bird


Beatrice Alexander-Howden, Kyla Brown, Justyna Cholewa-Waclaw, John Connelly, Dina De Sousa, Jacky Guy, Martha Koerner, Sabine Lagger, Matthew Lyst, Cara Merusi, Timo Quante, Jim Selfridge, Ruth Shah, Christine Struthers, Rebekah Tillotson
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CpG as a genomic signalling module

Adrian gives a brief overview of his research.

We study the influence of the short DNA sequence motif 5’CG (also known as CpG) on chromatin structure and gene expression. The frequency of this two-base pair sequence is highly variable, being under-represented in the great majority of the genome, but abundant in “CpG islands”, which mark the regulatory regions of most human genes. Our recent work indicates that CpG islands function as landing pads for proteins that recognise CpG in the unmethylated state and facilitate chromatin modification of the N-terminal tails of core histones. Using synthetic CpG island sequences lacking the ability to drive transcription, we find that CpG frequency is indeed the key motif responsible for recruitment of these chromatin marks. Other CpG island-like features are also required, however, as a high frequency of CpGs fails to induce characteristic chromatin modifications if embedded in DNA that is rich in the bases A and T. In fact A+T-rich DNA reliably induces DNA methylation, which blocks addition of other histone marks. This work establishes that the two prominent shared features of all mammalian CpG islands – G+C-richness and a high CpG frequency – are both required for their function.

Methylation of CpG islands, for example on the inactive X chromosome or at imprinted genes, excludes CpG binding proteins and allows access by proteins that specifically interact with methylated CpG. Such methyl-CpG binding proteins often associate with transcriptional corepressor complexes that facilitate the formation of silent chromatin. CpG islands therefore have the potential to participate in transcriptional switching during development. To map their methylation in the human brain, we used a biochemical method to retrieve densely methylated DNA from regions of the human brain followed by high throughput DNA sequencing. We were surprised to find that most brain regions display remarkably similar DNA methylation patterns, even when derived from different cell lineages. The conspicuous exception is cerebellum, which exhibits many differentially methylated regions compared with the rest of the brain. Interestingly these differences conform to a pattern, as cerebellar DNA with higher or lower levels of this DNA modification differ sharply in base composition. These results again suggest that DNA base composition – long considered to be a passive consequence of constraints on chromatin structure and metabolism – may act as a biological signal that affects the structure of the epigenome. We currently seek mediators of these effects, which may provide a “missing link” in our understanding of the function of DNA methylation.

Selected publications:

Illingworth RS, Gruenewald-Schneider U, De Sousa D, Webb S, Merusi  C, Kerr AR, James KD, Smith C, Walker R, Andrews R, Bird AP. Inter-individual variability contrasts with regional homogeneity in the human brain DNA methylome. Nucleic acids research. 2015.

Wachter E, Quante T, Merusi  C, Arczewska A, Stewart F, Webb S, Bird A. Synthetic CpG islands reveal DNA sequence determinants of chromatin structure. eLife. 2014; 3.

Lyst MJ, Bird A. Rett syndrome: a complex disorder with simple roots. Nature Reviews Genetics. 2015.

Figure 1. CpG islands (blue dots) are distinct from the rest of the genome (grey dots) in both G+C content (%G+C) and their observed-over-expected frequency of CpG (CG[o/e]).

Figure 2. Examples of CpG island promoters. CpGs are represented by vertical strokes and red boxes show the first exon only of the genes concerned.

Figure 3. Base composition of differentially methylated regions (DMRs) in the human cerebellum in comparison with other brain regions. Blue bars: hypo-methylated; red bars: hyper-methylated.