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