2% of the genome Moreover, 985% of the occupancy sites of trans

2% of the genome. Moreover, 98.5% of the occupancy sites of transcription factors previously mapped by ChIP-seq lie within accessible chromatin defined by DNase I hotspots, reaffirming their likely cell-specific regulatory role. Histone modifications associated with regulatory elements (e.g., methylation,

acetylation) were also assayed by ChIP-seq, and were found to be common in the genome (56.1%). Finally, one of the principal purposes of ENCODE was to determine what proportion of this noncoding genome is transcribed, and in which cell/tissue types. MEK inhibitor Djebali et al.15 demonstrate with ultra-deep RNA sequencing that about 75% of the genome is transcribed to RNA at some point in certain cell types. Therefore, the majority of RNA in a cell is never translated to protein, but may play important regulatory functions. Moreover, the expression of RNA transcripts from genes is not uniform—most genes express more than one isoform of a transcript, with an average of 10-12 expressed isoforms per gene per cell

line. This remarkable finding p38 MAPK inhibitor has forced a re-think of our nomenclature of genomic organization, and in particular the gene as the fundamental building block of the genome. On the basis of the ENCODE data, it can be argued that the transcript is the basic unit of genomic organization, describing genes which are transcribed in different cellular environments under specific conditions. The ENCODE project has demonstrated that the vast majority of the human genome, although not coding for proteins, does contain important regions that bind proteins and RNA molecules which cooperate to regulate the function and expression of protein-coding genes. Additionally,

it seems that transcription is a lot more widespread than previously thought, learn more with large numbers of noncoding RNA molecules with potential regulatory roles. The immediate implications of these findings are that genome-wide approaches to determining disease risk and finding targets for therapy require reevaluation in this light. ENCODE demonstrates that noncoding regions must be considered when interpreting GWAS findings, and provides a strong basis for reinterpreting previous GWAS results. Furthermore, as mentioned above, the results of ENCODE suggest that exome-sequencing studies focusing on protein-coding sequences risk missing crucial parts of the genome and the ability to identify true causal variants. Although the prospect of characterization and validation of this new tier of genomic control is daunting, it does provide opportunity both in terms of technologies and therapeutics. Just as ENCODE disseminated technologies such as ChIP-seq and RNA-seq over the last decade, so technologies of gene editing such as zinc-finger and TAL effector-like nucleases are now scalable, and thus functional elements can be validated on a large scale.

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