The Changing Face of Genomics

A report on the 5th annual Advances in Genome Biology and Technology (AGBT) and Automation in DNA Mapping and Sequencing (AMS) meeting, Marco Island, USA, 4-7 February 2004

ChromHMM: automating chromatin-state discovery and characterization

To the Editor: Chromatin-state annotation using combinations of chromatin modification patterns has emerged as a powerful approach for discovering regulatory regions and their cell type–specific activity patterns and for interpreting disease-association studies1, 2, 3, 4, 5. However, the computational challenge of learning chromatin-state models from large numbers of chromatin modification datasets in multiple cell types still requires extensive bioinformatics expertise. To address this challenge, we developed ChromHMM, an automated computational system for learning chromatin states, characterizing their biological functions and correlations with large-scale functional datasets and visualizing the resulting genome-wide maps of chromatin-state annotations.Massachusetts Institute of Technology. Computational and Systems Biology InitiativeNational Science Foundation (U.S.) (postdoctoral fellowship 0905968)National Institutes of Health (U.S.) (1-RC1- HG005334)National Institutes of Health (U.S.) (1 U54 HG004570

Interplay between chromatin state, regulator binding, and regulatory motifs in six human cell types

The regions bound by sequence-specific transcription factors can be highly variable across different cell types despite the static nature of the underlying genome sequence. This has been partly attributed to changes in chromatin accessibility, but a systematic picture has been hindered by the lack of large-scale data sets. Here, we use 456 binding experiments for 119 regulators and 84 chromatin maps generated by the ENCODE in six human cell types, and relate those to a global map of regulatory motif instances for these factors. We find specific and robust chromatin state preferences for each regulator beyond the previously reported open-chromatin association, suggesting a much richer chromatin landscape beyond simple accessibility. The preferentially bound chromatin states of regulators were enriched for sequence motifs of regulators relative to all states, suggesting that these preferences are at least partly encoded by the genomic sequence. Relative to all regions bound by a regulator, however, regulatory motifs were surprisingly depleted in the regulator's preferentially bound states, suggesting additional non-sequence-specific binding beyond the level predicted by the regulatory motifs. Such permissive binding was largely restricted to open-chromatin regions showing histone modification marks characteristic of active enhancer and promoter regions, whereas open-chromatin regions lacking such marks did not show permissive binding. Lastly, the vast majority of cobinding of regulator pairs is predicted by the chromatin state preferences of individual regulators. Overall, our results suggest a joint role of sequence motifs and specific chromatin states beyond mere accessibility in mediating regulator binding dynamics across different cell types.National Institutes of Health (U.S.) (Grant R01HG004037)National Institutes of Health (U.S.) (Grant RC1HG005334

Evidence of Abundant Purifying Selection in Humans for Recently Acquired Regulatory Functions

Although only 5% of the human genome is conserved across mammals, a substantially larger portion is biochemically active, raising the question of whether the additional elements evolve neutrally or confer a lineage-specific fitness advantage. To address this question, we integrate human variation information from the 1000 Genomes Project and activity data from the ENCODE Project. A broad range of transcribed and regulatory nonconserved elements show decreased human diversity, suggesting lineage-specific purifying selection. Conversely, conserved elements lacking activity show increased human diversity, suggesting that some recently became nonfunctional. Regulatory elements under human constraint in nonconserved regions were found near color vision and nerve-growth genes, consistent with purifying selection for recently evolved functions. Our results suggest continued turnover in regulatory regions, with at least an additional 4% of the human genome subject to lineage-specific constraint.National Institutes of Health (U.S.) (Grant R01HG004037)National Institutes of Health (U.S.) (Grant RC1HG005334)National Science Foundation (U.S.) (CAREER Grant 0644282

Sequences to systems

A report of the seventh annual meeting on Systems Biology: Global Regulation of Gene Expression, 23-27 March 2010, Cold Spring Harbor, USA

Large-scale discovery and validation of functional elements in the human genome

A report on the genomics workshop 'Identification of Functional Elements in Mammalian Genomes', Cold Spring Harbor, New York, 11-13 November 2004

Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals

Long intergenic noncoding RNAs (lincRNAs) play diverse regulatory roles in human development and disease, but little is known about their evolutionary history and constraint. Here, we characterize human lincRNA expression patterns in nine tissues across six mammalian species and multiple individuals. Of the 1898 human lincRNAs expressed in these tissues, we find orthologous transcripts for 80% in chimpanzee, 63% in rhesus, 39% in cow, 38% in mouse, and 35% in rat. Mammalian-expressed lincRNAs show remarkably strong conservation of tissue specificity, suggesting that it is selectively maintained. In contrast, abundant splice-site turnover suggests that exact splice sites are not critical. Relative to evolutionarily young lincRNAs, mammalian-expressed lincRNAs show higher primary sequence conservation in their promoters and exons, increased proximity to protein-coding genes enriched for tissue-specific functions, fewer repeat elements, and more frequent single-exon transcripts. Remarkably, we find that ∼20% of human lincRNAs are not expressed beyond chimpanzee and are undetectable even in rhesus. These hominid-specific lincRNAs are more tissue specific, enriched for testis, and faster evolving within the human lineage.National Institutes of Health (U.S.) (U54-HG004555)National Institutes of Health (U.S.) (R01-HG004037)National Science Foundation (U.S.) (CAREER 0644282