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Differential gene expression is the fundamental mechanism underlying animal development and cell differentiation. However, it is a challenge to identify comprehensively and accurately the DNA sequences that are required to regulate gene expression: namely, cis-regulatory modules (CRMs). Three major features, either singly or in combination, are used to predict CRMs: clusters of transcription factor binding site motifs, non-coding DNA that is under evolutionary constraint and biochemical marks associated with CRMs, such as histone modifications and protein occupancy. Source text: Hardison and Taylor, 2012.