Table 2.

Major Conceptual Advances Convey the Utility of Epigenome Maps

		Before Next-Gen Sequencing	The Next-Gen Sequencing Era	Future
CConcepts	DNA Methylation	Repressive mark at imprinted loci, transposons, and in x chromosome inactivation Found in active gene bodies Only dynamic in primordial germ cells and during fertilization	Metastable mark Active DNA demethylation by TET family proteins through 5hmC, 5fC, and 5caC Non-CpG methylation exists especially in ESCs and neurons Tissue specific methylation at distal regulatory elements	Comprehensive definition of epigenomic variation across all human cell types Define epigenomic variation in populations Discovering epigenetic signatures of disease Technology advances to enable single cell methylomes, Dnase-seq, ChIP-seq, and Hi-C A deeper understanding processes of epigenomic inheritabilty and reprogramming High-throughput functional validation of predicted enhancers Epigenome engineering Improved computational analysis and visualization tools
	Histone Modification	Marks that correlate with promoters and gene bodies H3K9me3 is a mark of heterochromatin H3K27me3 is a mark of facultative heterochromatin Proposal of the Histone Code Hypothesis Bivalent Promoters marked by H3K4me3/H3K27me3 Unique chromatin signature of enhancers defined as H3K4me1	Over 130 different histone modifications have been identified Identification of novel ncRNAs by promoter and gene body chromatin signatures Active enhancers are marked by H3K27ac or H4K16ac Poised enhancers are marked by H3K4me1 alone or in combination with H3K27me3 Expansion of repressive chromatin blocks during differentiation Combinations of chromatin marks define a limited number of chromatin states
	Chromatin Structure	Nucleosome maps only in yeast, fly DHSs correlate with TF binding sites and regulatory elements	Nucleosomes in human genome are mostly ordered Nucleosomes are well positioned around regulatory regions DHSs predict enhancer-promoter pairs and cell types affected in disease
	Nuclear Architecture	Identification of chromosome territories, LADS, and transcription factories with FISH Few validated enhancer-promoter interacting pairs	Identification of sub-TADs, TADs and chromosome compartments Chromosome-wide maps of enhancer, promoter, and insulator interacting pairs