Genome-wide Discovery and Characterization of Chromatin S tates

1. Genome-wide Discovery and Characterization of Chromatin States Jason Ernst Kellis Lab/Bernstein ENCODE group CSAIL MIT and Broad Institute

2. Outline • Overview of ChromHMM for discovering chromatin states Application to 41 chromatin marks in CD4+T cells • Extending ChromHMM to multiple cell types  Application to Bernstein ENCODE Data • Extending ChromHMM to integrate diverse data types  Application to ENCODE Consortium Data

3. Outline • Overview of ChromHMM for discovering chromatin states Application to 41 chromatin marks in CD4+T cells • Extending ChromHMM to multiple cell types  Application to Bernstein ENCODE Data • Extending ChromHMM to integrate diverse data types  Application to ENCODE Consortium Data

4. Cartoon Illustration of ChromHMM Transcription Start Site Enhancer DNA Transcribed Region Observed Chromatin Marks K4me3 K4me3 K4me1 K4me1 K36me3 K36me3 K36me3 K36me3 e.g. H3K4me3 K27ac K4me1 Most likely Hidden State 5 2 1 3 5 5 6 6 6 6 4 6 High Probability Chromatin Marks in State 0.8 0.8 1: 0.7 200bp intervals 4: All probabilities are learned from the data K27ac K4me1 K4me1 0.9 0.8 2: 5: K4me1 K4me3 3: 6: 0.9 0.9 K4me3 K36me3

5. Chromatin Marks from (Barski et al, Cell 2007; Wang et al Nature Genetics, 2008); DNAseI hypersensitivity from (Boyle et al, Cell 2008); TF binding enrichment computed based on 14 published TF binding experiments; Expression Data from (Su et al, PNAS 2005)

6. Transition Matrix State To State From

7. Core Promoter States Proportion of State Different promoter states show distinct functional enrichment Distance to TSS

8. Transcribed Regions Enrichment (decr.) Enrichment (decr.) Percentage of Gene Length Position relative to exon start Enrichment (incr.) Enrichment (incr.)

9. Intergenic Active Regions Fold Enrichment Percentage of Gene Length Relative to TSS

10. Large-scale repressed and repetitive regions Specific repeat elements enriched for specific states Transition Matrix snapshot State From State To Probability of transition

11. Marks that have been profiled in several ENCODE cell types by the Broad Institute (PI: Bernstein)

12. Outline • Overview of ChromHMM for discovering chromatin states Application to 41 chromatin marks in CD4+T cells • Extending ChromHMM to multiple cell types  Application to Bernstein ENCODE Data • Extending ChromHMM to integrate diverse data types  Application to ENCODE Consortium Data

13. 10 State learned from three ENCODE cell lines Enrichment for HUVEC (other cell types similar) Model learned from K562, HUVEC, NHEK data

14. Comparing chromatin states across cell types HUVEC NHEK K562 Pairwise state fold enrichments Proportion of genome K562 CTCF island state (State 9) highly stable across cell types HUVEC NHEK

15. Comparing chromatin states across cell types HUVEC NHEK K562 K562 HUVEC GO Enrichment for TSS in Active promoter state (1) in NHEK and unmodified state (7) in HUVEC NHEK NHEK HUVEC

16. Extending ChromHMM to Multiple Cell Types Concatenate Genomes Stack Features Independent Models K562 Genome Genome Gm12878 K562 H3K4me3 in K562 H3K4me3 H3K4me3 H3K27me3 H3K4me3 in Gm12878 H3K27me3 H3K27me3 in K562 Gm12878 Genome H3K27me3 in Gm12878 H3K4me3 H3K27me3

17. Outline • Overview of ChromHMM for discovering chromatin states Application to 41 chromatin marks in CD4+T cells • Extending ChromHMM to multiple cell types  Application to Bernstein ENCODE Data • Extending ChromHMM to integrate diverse data types  Application to ENCODE Consortium Data

18. Integrating Diverse Data with ChromHMM Transcription Start Site Enhancer DNA Transcribed Region Observed Chromatin Marks K4me3 K4me3 K4me1 K4me1 K36me3 K36me3 K36me3 K36me3 e.g. H3K4me3 K27ac K4me1 Additional Genomic Datasets cMyc e.g. cMyc DNaseI DNaseI DNaseI Most likely Hidden State 5 3 5 5 6 6 6 1 2 6 4 6 High Probability Chromatin Marks in State 0.8 0.8 0.7 1: 0.7 4: 200bp intervals K27ac K4me1 DNaseI K4me1 0.9 0.8 2: 0.7 5: DNaseI K4me3 K4me1 3: 6: 0.9 0.8 0.9 0.9 cMyc DNaseI K4me3 K36me3

19. Integrative Analysis on ENCODE Consortium Data

20. State 21 Concentrated near Transcription Termination Sites Distribution Relative to nearest RefSeq TTS

21. State 0 Highly Specific to TSS Distribution Relative to nearest RefSeq TSS

22. TSS of Genes of Distinct Function Enriched in Different States

23. TSS of Genes of Distinct Function Enriched in Different States

24. TSS of Genes of Distinct Function Enriched in Different States

25. TSS of Genes of Distinct Function Enriched in Different States

26. Summary • ChromHMM learns de-novo chromatin states from a large number of chromatin marks • Applications: • Single cell type, lots of marks  Chromatin states • Multiple cell types  Chromatin dynamics • Diverse input tracks  Data integration • Going forward: • Integration with regulatory motifs • Sequence determinants of chromatin / expression

27. Acknowledgements Members of the Kellis Lab and Bernstein ENCODE group • Manolis Kellis • Bradley Bernstein • Chuck Epstein • Pouya Kheradpour • Michael Lin • Tarjei Mikkelsen • Noam Shoresh Funding: NIH/NHGRI

28. Questions?