Dinh/Dinh 2012/NOTES/2012-1-6
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Regulatory segmentation and aberrant methylation localization[edit]
- Continuing from http://genome-tech.ucsd.edu/LabNotes/index.php/Dinh/Dinh_2012/NOTES/2012-1-5
- I decided to check all of our aberrantly methylated CpGs in the 67 shared aberrantly methylated genes in all 9 tissues which was characterized in the paper:
- GM12878 B-lymphoblastoid cell
- H1 human embryonic stem cell
- K562 - erythrocytic leukemia cell
- HepG2 - hepatocellular carcinoma cell
- Huvec - umbilical vein endothelial cell
- Hsmm - skeletal muscle myoblast
- Nhlf - normal lung fibroblast
- Nhek - normal epidermal keratinocytes
- Hmec - mammary epithelial cell
- The idea of the paper was to segment the genome into regions characterized by maximal probability of chromatin state using a Hidden Markov Model and available genome-wide ChIP-seq data sets.
- Here's a figure from the paper describing the 15 chromatin states and their profiles from chromatin, transcription factor binding, and expression data:
File:Chromatin states nature09906.png
- We have 710,143 CpGs which were captured overall by BSPP and 1,318 CpGs which were associated with 67 aberrantly methylated genes. I simply took the count of CpGs for each chromatin state.
- Note that there is no overlapping state in this data.
- Comparing the absolute counts:
File:Chromatin states absolute counts.png
- Comparing the ratios against background:
File:Chromatin states enrichmentratio.png
- (To get p-values, I still need to permute the 1318 CpGs.)
Discussion[edit]
- The distribution of CpGs in the six somatic cells are nearly identical whereas in the pluripotent and diseased cells they are dramatically different. Thus, these CpGs are clearly localized in regions which characterize pluripotent or diseased chromatin states.
- The changes in methylation and in the chromatin states were together necessary in these regions.
- Aberrantly methylated genes appear to be enriched in the heterochromatin of normal somatic cell types
- Aberrantly methylated genes appear to be enriched in the repressed or weak transcription regions of diseased cells (carcinoma and leukaemia cells)
- Aberrantly methylated genes appear to be enriched in the poised promoter and weak enhancer regions of Hues1 cells
- Taken together, it appears that the regions of shared aberrantly methylation are inactive in normal somatic cell types and in order to become pluripotent, these regions had to become available for transcription factor binding.
- Although we observed only incomplete or inaccurate DNA methylation, it is possible that it have occurred together with incomplete chromatin state changes leading to the aberrant gene expression that we observed for the 67 genes.
Raw count data[edit]
- Distribution of 710,143 CpG captured (normal background)
index | Gm12878 | Hues1 | HepG2 | Hmec | Hsmm | Huvec | K562 | NheK | Nhlf |
1 Active Promoter | 155134 | 98091 | 149234 | 140441 | 144761 | 127362 | 138195 | 160806 | 163605 |
2 Weak Promoter | 54647 | 99543 | 84351 | 66539 | 81877 | 52306 | 42421 | 48560 | 57918 |
3 Poised Promoter | 33318 | 112181 | 23191 | 30444 | 30738 | 41241 | 11188 | 48508 | 29617 |
4 Strong Enhancer | 25706 | 6502 | 20732 | 40113 | 28953 | 60847 | 38701 | 41087 | 23602 |
5 Strong Enhancer | 7196 | 5479 | 3663 | 17130 | 11368 | 12034 | 6565 | 10623 | 17517 |
6 Weak Enhancer | 25715 | 39832 | 26077 | 36734 | 24487 | 17789 | 24145 | 22473 | 23372 |
7 Weak Enhancer | 14734 | 29256 | 8412 | 18515 | 12843 | 12150 | 18463 | 11100 | 11527 |
8 Insulator | 23949 | 22124 | 15593 | 16184 | 19338 | 22376 | 27500 | 21652 | 25477 |
9 Txn Transition | 7427 | 16341 | 13422 | 6501 | 12486 | 6713 | 13635 | 9558 | 7391 |
10 Txn Elongation | 20125 | 14995 | 24206 | 17706 | 26627 | 17901 | 15561 | 25700 | 30073 |
11 Weak Txn | 45008 | 83606 | 58774 | 58240 | 64388 | 50153 | 63965 | 48396 | 43340 |
12 Repressed | 84516 | 23657 | 75330 | 56657 | 71052 | 89313 | 105331 | 95927 | 95739 |
13 Heterochrom/lo | 210173 | 155437 | 204772 | 203470 | 177279 | 196785 | 197883 | 163663 | 178993 |
14 Repetitive/CNV | 1740 | 1961 | 1242 | 834 | 2993 | 1925 | 3683 | 1215 | 1088 |
15 Repetitive/CNV | 755 | 1138 | 1144 | 635 | 953 | 1248 | 2907 | 875 | 884 |
total | 710143 | 710143 | 710143 | 710143 | 710143 | 710143 | 710143 | 710143 | 710143 |
- Distribution of 1,318 aberrantly methylated CpGs in 67 shared genes
index | Gm12878 | Hues1 | HepG2 | Hmec | Hsmm | Huvec | K562 | Nhek | Nhlf |
1 Active Promoter | 56 | 9 | 92 | 65 | 100 | 41 | 45 | 89 | 92 |
2 Weak Promoter | 25 | 95 | 42 | 30 | 37 | 42 | 37 | 47 | 25 |
3 Poised Promoter | 19 | 302 | 32 | 50 | 80 | 67 | 23 | 91 | 69 |
4 Strong Enhancer | 42 | 0 | 12 | 28 | 43 | 80 | 52 | 46 | 34 |
5 Strong Enhancer | 9 | 7 | 4 | 22 | 25 | 18 | 3 | 10 | 40 |
6 Weak Enhancer | 19 | 180 | 25 | 40 | 27 | 13 | 13 | 12 | 25 |
7 Weak Enhancer | 22 | 59 | 22 | 13 | 16 | 5 | 9 | 6 | 11 |
8 Insulator | 75 | 71 | 54 | 44 | 73 | 77 | 96 | 57 | 56 |
9 Txn Transition | 5 | 28 | 49 | 0 | 3 | 5 | 13 | 4 | 5 |
10 Txn Elongation | 26 | 4 | 46 | 21 | 26 | 15 | 2 | 48 | 82 |
11 Weak Txn | 70 | 131 | 267 | 90 | 107 | 64 | 107 | 42 | 42 |
12 Repressed | 175 | 88 | 162 | 233 | 148 | 204 | 448 | 242 | 192 |
13 Heterochrom/lo | 775 | 342 | 498 | 682 | 632 | 687 | 464 | 624 | 645 |
14 Repetitive/CNV | 0 | 2 | 13 | 0 | 1 | 0 | 6 | 0 | 0 |
total | 1318 | 1318 | 1318 | 1318 | 1318 | 1318 | 1318 | 1318 | 1318 |