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Epigenetic domains found in mouse embryonic stem cells via a hidden Markov model.

Larson JL, Yuan GC - BMC Bioinformatics (2010)

Bottom Line: Recent studies have shown significant epigenetic patterns associated with developmental stages and diseases.We found that each type of domain is associated with distinct biological functions and structural changes during early cell differentiation.The HMM approach successfully detects domains of consistent epigenetic patterns from ChIP-seq data, providing new insights into the role of epigenetics in long-range gene regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

ABSTRACT

Background: Epigenetics is an important layer of transcriptional control necessary for cell-type specific gene regulation. Recent studies have shown significant epigenetic patterns associated with developmental stages and diseases. However, previous studies have been mostly limited to focal epigenetic patterns, whereas methods for analyzing large-scale organizations are still lacking.

Results: We developed a hidden Markov model (HMM) approach for detecting the types and locations of epigenetic domains from multiple histone modifications. We used this method to analyze a published ChIP-seq dataset of five histone modification marks (H3K4me2, H3K4me3, H3K27me3, H3K9me3, and H3K36me3) in mouse embryonic stem (ES) cells. We identified three types of domains, corresponding to active, non-active, and states. In total, our three-state HMM identified 258 domains in the mouse genome containing 9.6 genes on average. These domains were validated by a number of criteria. The largest domains correspond to olfactory receptor (OR) gene clusters. Each Hox gene cluster also forms a separate epigenetic domain. We found that each type of domain is associated with distinct biological functions and structural changes during early cell differentiation.

Conclusions: The HMM approach successfully detects domains of consistent epigenetic patterns from ChIP-seq data, providing new insights into the role of epigenetics in long-range gene regulation.

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Heatmaps of known gene clusters. The 35 gene region on Ch6 from Npy to 2410066E13Rik (49,772,728 to 54,650,400) as depictured as a heatmap of histone modification and gene expression for (a) the ES cell line and (c) ES and NP cell lines. The 250 gene region on Ch7 from Art2a to Insc (108,701,290-121,993,728) as depictured as a heatmap of histone modification and gene expression for (b) the ES cell line and (d) ES and NP cell lines. For all figures on the left (a and c), cluster state assignment is given in the first and second tracks and HMM state assignments are in the third and fourth tracks (red for active state, blue for non-active state, yellow for  state). For figures on the right (b and d), NP HMM state assignment is given in the first and second tracks and ES HMM state assignments are in the third and fourth tracks. Whether (black) or not (white) a gene is a respective gene cluster in shown in the bottom track in all figures.
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Figure 6: Heatmaps of known gene clusters. The 35 gene region on Ch6 from Npy to 2410066E13Rik (49,772,728 to 54,650,400) as depictured as a heatmap of histone modification and gene expression for (a) the ES cell line and (c) ES and NP cell lines. The 250 gene region on Ch7 from Art2a to Insc (108,701,290-121,993,728) as depictured as a heatmap of histone modification and gene expression for (b) the ES cell line and (d) ES and NP cell lines. For all figures on the left (a and c), cluster state assignment is given in the first and second tracks and HMM state assignments are in the third and fourth tracks (red for active state, blue for non-active state, yellow for state). For figures on the right (b and d), NP HMM state assignment is given in the first and second tracks and ES HMM state assignments are in the third and fourth tracks. Whether (black) or not (white) a gene is a respective gene cluster in shown in the bottom track in all figures.

Mentions: The Hox gene clusters are a well-described epigenetic domain family. These genes regulate the anterior-posterior axis of metazoan organisms and are expressed in a sequential order during cell differentiation. In ES cells, the Hox genes are targeted by the Polycomb group (PcG) proteins and associated with bivalent domains [12,28]. Our method correctly detected each of the four Hox clusters to be in a non-active and significant domain. The results for the Hoxa cluster on chromosome (Ch) 6 are shown in Figure 6a. Simple K-means clustering failed to capture these state assignments.


Epigenetic domains found in mouse embryonic stem cells via a hidden Markov model.

Larson JL, Yuan GC - BMC Bioinformatics (2010)

Heatmaps of known gene clusters. The 35 gene region on Ch6 from Npy to 2410066E13Rik (49,772,728 to 54,650,400) as depictured as a heatmap of histone modification and gene expression for (a) the ES cell line and (c) ES and NP cell lines. The 250 gene region on Ch7 from Art2a to Insc (108,701,290-121,993,728) as depictured as a heatmap of histone modification and gene expression for (b) the ES cell line and (d) ES and NP cell lines. For all figures on the left (a and c), cluster state assignment is given in the first and second tracks and HMM state assignments are in the third and fourth tracks (red for active state, blue for non-active state, yellow for  state). For figures on the right (b and d), NP HMM state assignment is given in the first and second tracks and ES HMM state assignments are in the third and fourth tracks. Whether (black) or not (white) a gene is a respective gene cluster in shown in the bottom track in all figures.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992069&req=5

Figure 6: Heatmaps of known gene clusters. The 35 gene region on Ch6 from Npy to 2410066E13Rik (49,772,728 to 54,650,400) as depictured as a heatmap of histone modification and gene expression for (a) the ES cell line and (c) ES and NP cell lines. The 250 gene region on Ch7 from Art2a to Insc (108,701,290-121,993,728) as depictured as a heatmap of histone modification and gene expression for (b) the ES cell line and (d) ES and NP cell lines. For all figures on the left (a and c), cluster state assignment is given in the first and second tracks and HMM state assignments are in the third and fourth tracks (red for active state, blue for non-active state, yellow for state). For figures on the right (b and d), NP HMM state assignment is given in the first and second tracks and ES HMM state assignments are in the third and fourth tracks. Whether (black) or not (white) a gene is a respective gene cluster in shown in the bottom track in all figures.
Mentions: The Hox gene clusters are a well-described epigenetic domain family. These genes regulate the anterior-posterior axis of metazoan organisms and are expressed in a sequential order during cell differentiation. In ES cells, the Hox genes are targeted by the Polycomb group (PcG) proteins and associated with bivalent domains [12,28]. Our method correctly detected each of the four Hox clusters to be in a non-active and significant domain. The results for the Hoxa cluster on chromosome (Ch) 6 are shown in Figure 6a. Simple K-means clustering failed to capture these state assignments.

Bottom Line: Recent studies have shown significant epigenetic patterns associated with developmental stages and diseases.We found that each type of domain is associated with distinct biological functions and structural changes during early cell differentiation.The HMM approach successfully detects domains of consistent epigenetic patterns from ChIP-seq data, providing new insights into the role of epigenetics in long-range gene regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

ABSTRACT

Background: Epigenetics is an important layer of transcriptional control necessary for cell-type specific gene regulation. Recent studies have shown significant epigenetic patterns associated with developmental stages and diseases. However, previous studies have been mostly limited to focal epigenetic patterns, whereas methods for analyzing large-scale organizations are still lacking.

Results: We developed a hidden Markov model (HMM) approach for detecting the types and locations of epigenetic domains from multiple histone modifications. We used this method to analyze a published ChIP-seq dataset of five histone modification marks (H3K4me2, H3K4me3, H3K27me3, H3K9me3, and H3K36me3) in mouse embryonic stem (ES) cells. We identified three types of domains, corresponding to active, non-active, and states. In total, our three-state HMM identified 258 domains in the mouse genome containing 9.6 genes on average. These domains were validated by a number of criteria. The largest domains correspond to olfactory receptor (OR) gene clusters. Each Hox gene cluster also forms a separate epigenetic domain. We found that each type of domain is associated with distinct biological functions and structural changes during early cell differentiation.

Conclusions: The HMM approach successfully detects domains of consistent epigenetic patterns from ChIP-seq data, providing new insights into the role of epigenetics in long-range gene regulation.

Show MeSH