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Histone H3k27ac Separates Active from Poised Enhancers and Predicts Developmental State

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Histone H3k27ac Separates Active from Poised Enhancers and Predicts Developmental State Histone H3K27ac separates active from poised SEE COMMENTARY enhancers and predicts developmental state Menno P. Creyghtona,1, Albert W. Chenga,b,1, G. Grant Welsteada, Tristan Kooistrac,d, Bryce W. Careya,e, Eveline J. Steinea,e, Jacob Hannaa, Michael A. Lodatoa,e, Garrett M. Framptona,e, Phillip A. Sharpd,e, Laurie A. Boyere, Richard A. Younga,e, and Rudolf Jaenischa,e,2 aWhitehead Institute for Biomedical Research, Cambridge, MA 02142; bComputational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02142; cDivision of Health Sciences and Technology, Harvard–Massachusetts Institute of Technology, Boston, MA 02115; dKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142; and eDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 Contributed by Rudolf Jaenisch, October 26, 2010 (sent for review September 29, 2010) Developmental programs are controlled by transcription factors and distal enhancers (13). Finally distal H3K4me1-enriched Stat1 chromatin regulators, which maintain specific gene expression binding sites become selectively activated upon INF-γ treatment programs through epigenetic modification of the genome. These of HeLa cells, suggesting that these regions maintain the po- regulatory events at enhancers contribute to the specificgene tential to become active (5). This raises the intriguing possibility expression programs that determine cell state and the potential that enhancers contain information about the current and future for differentiation into new cell types. Although enhancer elements developmental potential of a cell, as well as its ability to respond are known to be associated with certain histone modifications and to external cues. fi Here, we identify close to 135,000 candidate distal enhancer transcription factors, the relationship of these modi cations to gene fi expression and developmental state has not been clearly defined. regions in ve different cell types. In a candidate approach to Here we interrogate the epigenetic landscape of enhancer elements identify factors that could potentially discriminate between the various possible enhancer states, we establish H3K27ac as an in embryonic stem cells and several adult tissues in the mouse. We important enhancer mark that can distinguish between active and find that histone H3K27ac distinguishes active enhancers from poised enhancer elements. This mark can be deposited by both inactive/poised enhancer elements containing H3K4me1 alone. This p300 and CREB binding protein (CBP) (14) and is associated with indicates that the amount of actively used enhancers is lower than active promoters in mammalian cells (15). Using this modification previously anticipated. Furthermore, poised enhancer networks to distinguish poised from active enhancer networks allows us to provide clues to unrealized developmental programs. Finally, we make predictions on the developmental potency of the cell, as well show that enhancers are reset during nuclear reprogramming. as it current state. Furthermore, it suggests that the active global enhancer network of a cell is smaller than previously anticipated. he genome comprises a large number of noncoding DNA Tregulatory elements, including silencers, insulators, and en- Results hancer regions, that play important regulatory roles in maintain- H3K27ac Distinguishes Active from Inactive Enhancers. We first ing gene expression programs. Enhancers have emerged as key identified cell type-specific enhancers in murine ES cells using cis-regulatory elements that can affect gene transcription in- distal H3K4me1 histone marks identified by ChIP-Seq (Fig. 1A, dependent of their orientation or distance. Global identification Table S1, and SI Materials and Methods) using similar criteria as of these regions as well as their contribution to target gene ex- shown previously (5–9, 16). We identified 25,036 distal enhancer pression has been challenging because enhancers can often reside elements that are roughly equally distributed between introns thousands of base pairs away from their target of regulation (1, 2). and intergenic regions (Fig. S1A). To test the robustness of these Individual enhancers have been identified by detailed studies data we compared our results with a previously published of disease-related elements that reside in noncoding regions H3K4me1 data set in 129/C57BL6 F1 ES cells (17) and found outside of model genes (3), followed on a larger scale by com- that they displayed a remarkably similar distribution pattern parative genomics using ultra-conservation (4). These studies (Pearson correlation, 0.76; Fig. S1 B and C). Second ES cells unequivocally established specific cis-regulatory elements as from an inbred genetic background (C57BL6/N) yielded very important regulators of development and disease. Recently similar results (Pearson correlation, 0.77), indicating that cell efforts to globally identify enhancers have focused on the histone type-specific enhancers pattern the genome with high fidelity mark H3K4me1 to locate many cell type-specific enhancer sites with little effect from genetic background. (5–9). Analysis of human primary and tumor cell lines has shown Proximal gene expression was previously shown to be prefer- that enhancer regions identified by virtue of H3K4me1 enrich- entially affected by enhancer elements (11), and enhancers seem ment, as well as DNaseI hypersensitivity, display a cell type- to cluster near the genes they regulate (5). Similarly, the overall specific distribution across the genome (5, 10). Another study found that the histone acetyltransferase p300 is enriched at enhancers in fetal mouse tissues and found similar tissue-specific Author contributions: M.P.C., A.W.C., and R.J. designed research; M.P.C., A.W.C., G.G.W., marking of these elements. Notably, many of these enhancers B.W.C., E.J.S., J.H., and M.A.L. performed research; G.G.W., T.K., G.M.F., P.A.S., L.A.B., and were shown to contribute to transcriptional activity of proximal R.A.Y. contributed new reagents/analytic tools; M.P.C., A.W.C., T.K., and G.M.F. analyzed genes in a tissue-specific manner (11). data; and M.P.C., A.W.C., L.A.B., R.A.Y., and R.J. wrote the paper. Although most H3K4me1 marked enhancer regions displayed The authors declare no conflict of interest. activity when tested in reporter assays, a significant percentage This article is a PNAS Direct Submission. was not active (5, 11). One hypothesis is that H3K4me1 can mark Data deposition: Raw data are available online at the Gene Expression Omnibus (GEO) active enhancers as well as those in a poised or predetermined ascension viewer series, www.ncbi.nlm.nih.gov/geo (accession nos. GSE24164, GSE24165, state. Indeed, several lines of evidence support the existence of and GSE23907). poised enhancers. Lineage-specific enhancers that become acti- See Commentary on page 21240. vated upon differentiation are protected from DNA methylation 1M.P.C. and A.W.C. contributed equally to this work in the parental ES cells, where the enhancers are not yet active 2To whom correspondence should be addressed. E-mail: [email protected]. (12). Furthermore, large sets of inactive developmental genes in This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. SYSTEMS BIOLOGY hematopoietic stem cells are associated with H3K4me1-enriched 1073/pnas.1016071107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1016071107 PNAS | December 14, 2010 | vol. 107 | no. 50 | 21931–21936 A H3K4me1 H3K4me3 B C Fig. 1. H3K27ac is a good candidate to 100 100 distinguish active from inactive enhancer elements. (A) Heatmap of 25,036 putative le i le t i enhancers based on H3K4me1 enrichment t and H3K4me3 depletion in ES cells. Eight- percen percen kilobase pairs around the center of the en- hancer region are displayed. (B)Geneex- 0 0 pression of microarray data generated in duplicates in ES cells. Box-plots show all genes (All) and genes found associated with 25036 putave enhancers 25036 putave enhancers (H3K4me1+) either enriched (+) − Short RNA H3K27ac H3K4me1 or unenriched ( ) for Oct4 or (C) H3K27ac. D 40.00% E Solid bars of boxes display the 25–75% of ranked genes with the mean indicated as an 30.00% intersection. (D) Graph showing the per- centage of enhancers identified in A that − 20.00% are called bound at P =10 8 by the indicated ES enhancers ES factors or chromatin marks. (E)Heatmap 21166 TSSs 10.00% showing a composite of distal H3K27ac- and Percentage enrichment 0.00% H3K4me1-enriched regions ordered by pres- ence and absence of these two histone marks. Left: Occurrence of short RNA reads based on this distribution within a −8kbto +8 kb window (SI Materials and Methods). presence of the enhancers identified in this study correlated well 4.06E-7). These data indicate that H3K27ac is a good candidate with increased gene activity of proximal genes when we com- to discriminate between active and poised enhancer states. In pared these ChIP data with microarray expression data (Fig. 1 B support of this, we found that Oct4 (P = 1.8E-8) and Sox2 (P = and C; P = 4.4E-16). Consistent with its role as a master regu- 1.7E-8) are selectively enriched at H3K27ac-negative enhancers. lator of ES cell state, motif search analysis identified the Oct4 Because genes can be associated with multiple enhancers that (POU) binding domain at ES cell enhancers (P = 1.0E-250), are either H3K4me1+, H3K27ac+, or a combination of both, we suggesting a role for this transcription factor in enhancer
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