We were astonished to see two sentences in your Editorial on the International Human Epigenome Consortium (Nature 463, 587; 2010) that seem to disregard principles of gene regulation and of evolutionary and developmental biology that have been established during the past 50 years.

You say: “By 2004, large-scale genome projects were already indicating that genome sequences, within and across species, were too similar to be able to explain the diversity of life. It was instead clear that epigenetics — those changes to gene expression caused by chemical modification of DNA and its associated proteins — could explain much about how these similar genetic codes are expressed uniquely in different cells, in different environmental conditions and at different times.”

With respect to 'epigenomics', we wish to stress that chromatin 'marks' and local chemical modifications of DNA, such as methylation, are the consequences of DNA-sequence-specific interactions of proteins (and RNA) that recruit modifying enzymes to specific targets. They are thus directly dependent on the genomic sequence. Such marks are the effects of sequence-specific regulatory interactions, not the causes of cell-type-specific gene expression.

Gene regulation explains in outline, and in many cases in detail, how similar genomes give rise to different organisms. Self-maintaining loops of regulatory gene expression are switched on and off, producing the epigenetic effects that lie at the heart of development. Whereas the protein-coding toolkit is in part similar among species, the remainder of the genome, including almost all the regulatory sequence, is unique to each clade: therein lies the explanation for the diversity of animal life.

A letter signed by eight prominent scientists (not including us), and an associated petition signed by more than 50, went into these matters in greater detail, and expressed serious reservations about the scientific basis of the epigenome project. A modified version of the letter appeared in Science (H. D. Madhani et al. Science 322, 43–44; 2008) — the complete letter can be found at http://madhanilab.ucsf.edu/epigenomics.