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The epigenome, such as nucleosome structure and DNA methylation, regulates expression of genes. Searching for evolutionarily conserved sequence motifs essential for controlling the epigenome is a fundamental problem in biology. Collecting massive epigenome data has been becoming increasingly feasible because of the wide-spread availability of next-generation sequencing technology. Thus, there have been growing interests in the genome-wide analysis of the epigenome. There are some issues to be resolved. Care has to be taken to select samples so as to reduce false-positive findings. Processing enormous epigenome data is a computationally intensive task and needs a suite of software techniques such as suffix array, error correction, customizable data visualization, machine learning, and efficient database management. In this talk, I will overview these issues and their solutions, and discuss remaining bioinformatics problems.