SUPPLEMENTARY INFORMATION Archetypal transcriptional blocks underpin yeast gene regulation in response to changes in growth conditions David Talavera1*, Christopher J Kershaw2, Joseph L Costello2,#a, Lydia M Castelli2,#b, William Rowe3,#c, Paul FG Sims4, Mark P Ashe2, Chris M Grant2, Graham D Pavitt2*, Simon J Hubbard3*. * Corresponding authors
[email protected] (DT)
[email protected] (GDP)
[email protected] (SJH)
1
Supplementary Figures in this file S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12 S13 S14 S15 S16 S17 S18 S19 S20 S21 S22 S23 S24 S25 S26 S27
Decision tree in the assignment of instances to new or existing clusters. Relationship between clusters if changing the correlation threshold. Relationship between clusters if changing the linkage method. Relationship between clusters if changing the linkage method. Relationship between clusters if changing the linkage method. Relationship between clusters if applying normalization techniques to the downloaded data. Relationship between clusters if applying normalization techniques to the downloaded data. Analysis of common transcription regulation within and between BTRs. Characterization of PSRs. Response consistency within PSRs (top/bottom 10% RNAs). Response consistency within PSRs (top/ bottom 5% RNAs). Response consistency within PSRs (top/ bottom 1% RNAs). Biological processes affected by consistent stress response (top/ bottom 10% RNAs). Biological processes affected by consistent stress response (top/ bottom 1% RNAs). Characterization of BTRs. Biological processes overrepresented within BTRs (whole heatmap). Biological processes overrepresented within BTRs (zoomed in). Functional similarity within BTRs. Significance of interactions within BTRs. Regulation of transcription within and between BTRs. BTRs suffering extreme expression changes. Multi-dimensional scaling of transcriptomes from yeast grown under different stress conditions. Similarity of transcriptional response to stress (stress vs. control). Common stress responses. Magnitude of transcriptional stress-response. Biological processes affected by stress response. Use of BTRs for functional annotation.
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2
Other files containing supporting information S1 File. General description of data and clustering results. S2 File. Matrix containing the log-fold changes for each experiment. S3 File. Matrix containing the Pearson correlations between experiments. S4 File. Matrix containing the Pearson correlations between RNAs. S5 File. Alternative PSR clusters. S6 File. In-detail description of PSRs analysed in the paper. S7 File. Composition of PSR subsets analysed in the paper. S8 File. Biological processes associated with subsets of PSRs. S9 File. Composition of BTRs analysed in the paper. S10 File. Biological processes associated with BTRs. S11 File. edgeR results for NGS-based transcriptomic analyses.
3
Yes
Do nothing
Select two instances
Are both instances in the same cluster?
No
Are the members of each cluster connected to all the members of the other cluster
No Do nothing
Yes
Yes
Are any of the instances already in a cluster?
Yes
No
Are both instances already in a cluster?
Merge both clusters
No
Yes
Do nothing
No
Create a new cluster containing the two instances
Is the nonclustered instance connected to all the members of the cluster
Add instance to the existing cluster
4
S1 Fig. Decision tree in the assignment of instances to new or existing clusters.
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● 80 ● 42 ● 142 ● 65 ● 57 ● 81 ● 143 ● 47 ● 21 ● 76 ● 75 ● 177 ● 74 ● 17 ● 93 ● 18 ● 99 ● 34 ● 197 ● 117 ● 151 ● 73 ● 141 ● 69 ● 109 ● 63 ● 85 ● 22 ● 20 ● 19 ● 8 ● 188 ● 59 ● 40 ● 39 ● 43 ● 7 ● 37 ● 36 ● 161 ● 150 ● 35 ● 217 ● 183 ● 33 ● 30 ● 29 ● 28 ● 26 ● 112 ● 24 ● 13 ●
118 ● 50 ● 68 ● 58 ● 28 52 63 100 ● ● ● ● 48 ● 46 ● 125 51 ● ● 98 139 62 ● ● ● 84 102 ● ● 32 ● 93 56 ● ● 27 50 12 ● ● ● 195 ● 47 25 ● ● 97 92 129 ● ● ● ● 24 46 209 165 174 ● ● ● ● 77 ● 134 ● 94 194 145 ● ● ● 96 45 91 55 96 ● ● ● ● ● 90 ● 209 140 166 ● ● ● 51 86 124 ● ● ● 78 ● 127 119 163 ● ● ● 87 61 138 122 54 ● ● ● ● ● 66 ● 204 115 160 ● ● ● 36 44 106 ● ● ● 77 83 94 175 ● ● ● ● 31 158 ● ● 59 135 ● ● 119 108 ● ● 49 82 157 ● ● ● 162 88 112 155 ● ● ● ● 67 ● 43 48 81 121 ● ● ● ● 149 192 104 ● ● ● 47 80 120 ● ● ● 98 187 145 ● ● ● 32 40 87 ● ● ● 183 105 91 139 180 ● ● ● ● ● 45 ● 131 169 85 ● ● ● 38 22 115 ● ● ● 77 41 168 ● ● ● 52 87 130 ● ● ● 102 ● 46 76 114 ● ● ● 33 34 129 83 167 ● ● ● ● ● 72 ● ● 103 72 133 223 ● ● ● 51 128 ● ● 20 56 ● ● 18 32 43 107 71 ● ● ● ● ● 120 159 75 ● ● ● 40 69 103 ● ● ● 145 ● 89 36 97 52 65 73 117 ● ● ● ● ● ● ● 105 ● 62 ● 29 21 86 63 138 ● ● ● ● ● 53 82 115 ● ● ● 28 15 111 ● ● ● 199 164 ● ● 60 156 ● ● 16 54 89 67 71 114 ● ● ● ● ● ● 4 ● 219 ● 17 26 134 59 131 ● ● ● ● ● 86 74 112 ● ● ● 108 25 130 ● ● ● 226 ● 110 151 153 ● ● ● 224 ● 78 24 30 55 104 66 146 ● ● ● ● ● ● ● 80 ● 118 ● 42 64 101 ● ● ● 50 ● 142 ● 23 14 68 ● ● ● 28 52 65 ● ● ● 58 ● 57 63 100 ● ● ● 13 22 48 ● ● ● 81 125 51 ● ● ● 12 21 46 ● ● ● 84 102 143 ● ● ● 139 20 98 139 62 ● ● ● ● ● 47 ● 18 11 27 50 32 ● ● ● ● ● 21 93 56 ● ● ● 74 12 ● ● 102 47 25 76 ● ● ● ● 16 195 ● ● 24 46 75 ● ● ● 10 154 97 92 129 ● ● ● ● ● 177 ● 77 ● 96 74 45 ● ● ● 94 ● 17 91 55 ● ● ● 90 ● 93 ● ● 51 86 124 ● ● 87 18 61 ● ● ● 127 S2 Fig. Relationship between clusters if changing the correlation threshold. ● 99 138 122 ● ● ● 36 44 66 ● ● ● 34 ● 106 ● 197 77 83 ● ● ● 119 31 ● ● 117 ● 162 108 0.4, in blue; 0.5, in yellow; 0.6 in red. The darkness of the lines represent ● ● 151 49 82 ● ● ● 43 88 ● ● 73 ● 48 81 121 ● ● ● 141 ● 32 40 47 80 120 ● ● ● ● ● 69 ● 87 the similarity of the clusters (Jaccard Index). ● 109 183 105 ● ● ● 38 22 45 ● ● ● 63 ● 115 ● 85 77 41 ● ● ● 52 ● 33 34 22 ● ● ● 46 76 114 ● ● ● 20 ● 72 ● 19 103 72 ● ● ● 18 32 51 ● ● ● 8 ● 43 107 71 ● ● ● 188 ● 89 36 40 69 103 ● ● ● ● ● 59 ● 97 52 65 ● ● ● 29 40 21 ● ● ● 62 ● 39 28 15 86 63 ● ● ● ● ● 53 ● 43 ● 16 54 199 164 ● ● ● ● 7 60 ● ● 89 67 ● ● 37 17 26 ● ● ● 219 ● 108 25 36 134 59 ● ● ● ● ● 86 ● 161 ● 226 ● 78 24 150 ● ● ● 224 ● 35 30 55 ● ● ● 80 ● 217 ● 42 ● 23 183 14 ● ● ● 142 ● 33 ● 28 52 65 ● ● ● 13 30 22 ● ● ● 57 ● 29 12 21 ● ● ● 81 125 51 ● ● ● 139 20 28 ● ● ● 84 102 143 ● ● ● 18 26 11 ● ● ● 47 ● 74 112 27 50 ● ● ● ● 102 21 ● ● 16 24 ● ● ● 47 25 76 ● ● 10 13 154 ● ● ● 24 46 75 ● ● ● 177 ● 96 74 45 ● ● ● 17 ● 93 ● 87 18 61 ● ● ● 99 ● 36 44 ● ● 34 ● 197 ● 119 ● 117 ● 162 ● 151 ● 43 ● 73 ● 141 ● 32 40 ● ● 69 ● 109 ● 38 22 ● ● 63 ● 85 ● 33 34 22 ● ● ● 20 ● 19 ● 18 32 ● ● 8 6 ● 188 ● 89 36 ● ● 59 ● 29 40 21 ● ● ● 39 28 15 ● ● ● 43 ● 64 ●
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● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● S6 Fig. Relationship between clusters if applying normalization techniques ● ● ● ● ● ● ● to the downloaded data. In red, the method described in the main text. In ● ● ● ● ● ● ● blue, clusters generated normalizing data with a Rank-based quantile ● ● ● ● ● ● ● ● normalization approach prior to the correlation calculation. The darkness ● ● ● ● ● ● ● of the lines show how similar are the clusters (Jaccard Index). ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 10 ● ● ● ● ● ● ● ● ● ● ● 209
220 140
194
80
183
196
166
181
163
179
160
106
158
154
155
166
149
148
145
138
139
172
131
123
● ● ● ● ● ● ● ● ● ● ● ●
44
42
90
119
147
74
73
43
92
157
72
87
40
57
110
170
71
78
38
34
104
116
69
72
101
105
117
137
77
84
115
128
76
114
110
112
132
70
98 74
93
102
60
88
92
19
39
32
26
52
29
24
178
28
32
53
26
22
55
25
21
59
50 77
54
176
108
153
24
102
101
27
38
61
134
36
34
41
63
98
87
37
94
65
100
91
182
36
103
200
23
52
49
114
68
109
56
22
47
21
15
86
130
133
129
145
128
112
122
111
120
156
117
137
115
128
114
110
112
157
110
170
104
116
101
105
83
83
51
54
82
91
50
44
81
23
47
58
118
46
33
97
45
35
77
84
44
42
76
90
119
147
18
17
74
73
43
92
16
14
72
87
40
57
10
7
71
78
38
34
69
72
182
36
37
65
70
36
34
41
93
102
19
63
60
39
32
26
52
29
24
178
28
32
53
26
22
55
25
21
88
92
50
91
59
77
54
176
153
87
101
102
108
24
38
27
61
200
114
52
103
23
68
86
49
109
83
83
82
91
18
20
98 74
63
80
100
98
65
55
94
132
174
56
22
47
51
54
21
15
50
44
174
125
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● S7 Fig. Relationship between clusters if applying normalization techniques ● ● ● ● ● ● ● ● ● ● ● to the downloaded data. In red, the method described in the main text. In ● ● ● ● ● ● ● ● ● ● blue, clusters generated normalizing data with a Spline-based quantile ● ● ● ● ● ● ● ● ● ● ● normalization approach prior to the correlation calculation. The darkness ● ● ● ● ● ● ● ● ● ● of the lines show how similar are the clusters (Jaccard Index). ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 11 ● ● ● ● ● ● ● ● ● ● ● ● ● ●
● ● ● ● ● ● ● ● ● 117
109
47
80
202
209
130 149
194
128
75
183 166
167 155
104 102 101
89
67
53 90
149
172
93
118
145
143
139
181
131
110
79
161
69
117
91
71
102
69
15
65
54
63
52
60
50
59
48
54
44
81
119
86
65
72
28
22
26
16
25
21
177
24
40 37
157
51
50
59
47
64
22
88
46
45
21
18
45
41
204
113
147
87
91
44
57
109
43
23
27
55
80
36
38
61
92 60
80
35
34
104
153
74
77
101
72
141
110
134
71
102
104
97
69
15
102
127
65
54
101
107
63
52
132
60
50
105
59
48
100
54
44
32 29
32
30
36
20
29
72
211
28
22
26
16
25
21
177
24
40 37
126
89
157
52
65
23
27
43
98
90
93
118
51
51
195
50
59
142
47
64
79
46
45
69
45
41
22
88
21
18
204 147
55
114 58
113
71
24
20
165
40
77
24
70
87
91
25
44
57
83
119
20
165
18
114 58
129
76
82
29
51
19
150
83
20
119
95
91
36
83
78
92
30
211
25
33
53
32
70
120
100
32 29
71
83 82
112
141
34
142
92
128
114
72
195
76
115
77
80
43
159
103
74
52
98
47
104
126
176
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128
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107
155
129
120
127
105
122
61
97
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160
38
134
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130
35
101
132
158
36
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163
205
60
77
95
112 110
43
103
115 114
92
10
18
10
16
17
10
148
A A
Jaccard Index =
C
BTRi
B B
A∩B A∪B
BTRi
BTRj
A
E
B
F
C
G
D
H
A
B
C
D
Jaccard Indexi = Median value of 6 comparisons
Jaccard Indexi,j = Median value of 16 comparisons
S8 Fig. Analysis of common transcription regulation within and between BTRs. A. Diagram showing the calculation of the Jaccard Index between two sets. B. Analysis of common TFs within a BTR containing 4 RNAs: the black lines represent the pairwise comparisons between the different sets of TFs (one for each RNA). C. Analysis of common TFs between two BTRs: the black lines represent all the pairwise comparisons between sets in different BTRs.
12
50 20 10 5 2
Number of experiments within PSRs
0.5
0.6
0.7
0.8
0.9
1.0
Median correlation within PSRs
S9 Fig. Characterization of PSRs. Scatterplot shows the distribution of PSRs based on their within-group similarity (median of pairwise correlations within a PSR), and number of experiments within. Intensity of grey dots represents the number of overlapping points: the darker, the greater the number. Top and side histograms show the overall distribution of PSRs according to each variable.
13
Top/Bottom 10% RNAs
40
20
300 200
60
100
Number of enriched RNAs
C
0
Number of experiments in PSR
A
20
40
60
80
Number of experiments
D
0
250 200
200 150 0
150
100
Number of enriched RNAs
300
50
Number of depleted RNAs
250
B 350
100
20
50
40
60
Number of experiments
E
200 250 300
150
150
100
Number of depleted RNAs
100
200
250
50
80
50
Number of depleted RNAs
0
18 25 51 60 98 110 128 139 155 158 160 209 21 28 46 69 71 76 81 86 117 120 130 131 163 166 183 194 10 16 20 43 72 93 82 101 104 115 129 149 22 29 45 47 74 80 54 77 83 112 119 44 65 145 23 102 38 63 26 36 40 59 24 122 52 114 50 32 91 92 34 87 55 100
0
350
PSRs
0
100
200
300
Number of enriched RNAs
S10 Fig. Response consistency within PSRs (top/bottom 10% RNAs). A. Number of experiments within each PSR, sorted in increasing order. B. Number of consistently depleted and enriched RNAs within each PSR, ordered as in A. CE. Relationship between number of experiments within PSR, number of enriched transcripts within PSR and number of depleted transcripts within PSR.
14
Top/Bottom 5% RNAs
40
20
150 100
60
50
Number of enriched RNAs
200
C
0
Number of experiments in PSR
A
20
40
60
80
Number of experiments
D
0
140 100 80 60 0
100
40
150
20
Number of depleted RNAs
Number of enriched RNAs
B
50 20
40
60
80
Number of experiments
E
140 100 80 60
18 25 51 60 98 110 128 139 155 158 160 209 21 28 46 69 71 76 81 86 117 120 130 131 163 166 183 194 10 16 20 43 72 93 82 101 104 115 129 149 22 29 45 47 74 80 54 77 83 112 119 44 65 145 23 102 38 63 26 36 40 59 24 122 52 114 50 32 91 92 34 87 55 100
0
150
40
100
20
50
Number of depleted RNAs
Number of depleted RNAs
0
PSRs
0
50
100
150
200
Number of enriched RNAs
S11 Fig. Response consistency within PSRs (top/ bottom 5% RNAs). A. Number of experiments within each PSR, sorted in increasing order. B. Number of consistently depleted and enriched RNAs within each PSR, ordered as in A. CE. Relationship between number of experiments within PSR, number of enriched transcripts within PSR and number of depleted transcripts within PSR.
15
Top/Bottom 1% RNAs
40
20
30 25 20 15 10
60
5
Number of enriched RNAs
C
0
Number of experiments in PSR
A
20
40
60
80
Number of experiments
D
0
20 15 10
20 15 10
25
0
Number of enriched RNAs
30
5
Number of depleted RNAs
25
B
5
20
40
60
80
Number of experiments
E
20 25
15
18 25 51 60 98 110 128 139 155 158 160 209 21 28 46 69 71 76 81 86 117 120 130 131 163 166 183 194 10 16 20 43 72 93 82 101 104 115 129 149 22 29 45 47 74 80 54 77 83 112 119 44 65 145 23 102 38 63 26 36 40 59 24 122 52 114 50 32 91 92 34 87 55 100
0
30
10
15
5
10
20
25
5
Number of depleted RNAs
Number of depleted RNAs
0
PSRs
0
5
10
15
20
25
30
Number of enriched RNAs
S12 Fig. Response consistency within PSRs (top/ bottom 1% RNAs). A. Number of experiments within each PSR, sorted in increasing order. B. Number of consistently depleted and enriched RNAs within each PSR, ordered as in A. CE. Relationship between number of experiments within PSR, number of enriched transcripts within PSR and number of depleted transcripts within PSR.
16
RNA synthesis, modification & transport
Ribosome biogenesis & translation
Environmental stress
transcription from RNA polymerase I promoter RNA modification tRNA processing transcription from RNA polymerase III promoter ribosomal subunit export from nucleus regulation of translation nucleobase−containing compound transport nuclear transport endosomal transport cytokinesis response to starvation membrane invagination vesicle organization DNA−templated transcription, initiation protein glycosylation cellular ion homeostasis snoRNA processing RNA catabolic process vitamin metabolic process response to osmotic stress regulation of DNA metabolic process DNA recombination organelle fission meiotic cell cycle sporulation protein phosphorylation tRNA aminoacylation for protein translation translational initiation chromosome segregation cellular response to DNA damage stimulus mitotic cell cycle telomere organization cytoskeleton organization chromatin organization regulation of organelle organization DNA repair regulation of protein modification process regulation of cell cycle DNA replication protein complex biogenesis amino acid transport organelle fusion nucleus organization signaling cell morphogenesis transposition pseudohyphal growth invasive growth in response to glucose limitation conjugation cell wall organization or biogenesis carbohydrate transport lipid transport lipid metabolic process cellular amino acid metabolic process rRNA processing ribosomal small subunit biogenesis ribosomal large subunit biogenesis ribosome assembly organelle assembly cytoplasmic translation mitochondrion organization mitochondrial translation transmembrane transport ion transport monocarboxylic acid metabolic process generation of precursor metabolites and energy cellular respiration response to oxidative stress response to chemical response to heat oligosaccharide metabolic process proteolysis involved in cellular protein catabolic process protein maturation protein folding nucleobase−containing small molecule metabolic process cofactor metabolic process carbohydrate metabolic process
Yeast modification
Resources limitation
PSRs
PSRs
Enriched
No change
Depleted
17
163 194 34 47 100 32 112 129 149 24 122 50 83 52 45 155 120 92 51 130 10 101 145 166 59 114 76 46 21 20 81 55 60 158 29 36 28 82 119 43 98 104 160 44 87 93 40 22 209 16 74 25 128 38 80 102 23 86 91 65 71 54 63 18 115 69 183 110 77 117 26 131 72 139
163 194 34 47 100 32 112 129 149 24 122 50 83 52 45 155 120 92 51 130 10 101 145 166 59 114 76 46 21 20 81 55 60 158 29 36 28 82 119 43 98 104 160 44 87 93 40 22 209 16 74 25 128 38 80 102 23 86 91 65 71 54 63 18 115 69 183 110 77 117 26 131 72 139
S13 Fig. Biological processes affected by consistent stress response (top/ bottom 10% RNAs). GO Slim terms overrepresented in the set of 10% mostenriched transcripts (red) or the set of 10% most-depleted transcripts (blue). All colouring as in Fig 3. The black squares describe the type of stresses the PSRs suffered. The order of both PSRs and biological processes depends on the hierarchical clustering of Euclidean distances calculated along the columns and rows respectively.
18
transmembrane transport ion transport organelle fusion nucleus organization cell morphogenesis signaling conjugation response to starvation nucleobase−containing small molecule metabolic process regulation of translation carbohydrate transport regulation of protein modification process DNA repair mitotic cell cycle cellular response to DNA damage stimulus protein phosphorylation meiotic cell cycle regulation of cell cycle chromatin organization lipid metabolic process cofactor metabolic process ribosomal subunit export from nucleus nuclear transport ribosomal large subunit biogenesis rRNA processing ribosomal small subunit biogenesis ribosome assembly organelle assembly cytoplasmic translation lipid transport cellular amino acid metabolic process oligosaccharide metabolic process carbohydrate metabolic process monocarboxylic acid metabolic process response to osmotic stress protein folding response to heat generation of precursor metabolites and energy cellular respiration response to oxidative stress response to chemical
Environmental stress Resources limitation Yeast modification
PSRs PSRs
Enriched
No change
Depleted
19
22 45 34 194 32 82 63 183 47 52 69 16 139 18 128 40 72 115 25 77 46 38 87 92 102 50 86 54 71 20 119 145 81 83 24 129 93 10 60 131 23 209
22 45 34 194 32 82 63 183 47 52 69 16 139 18 128 40 72 115 25 77 46 38 87 92 102 50 86 54 71 20 119 145 81 83 24 129 93 10 60 131 23 209
S14 Fig. Biological processes affected by consistent stress response (top/ bottom 1% RNAs). GO Slim terms overrepresented in the set of 1% mostenriched transcripts (red) or the set of 1% most-depleted transcripts (blue). All colouring as in Fig 3. The black squares describe the type of stresses the PSRs suffered. The order of both PSRs and biological processes depends on the hierarchical clustering of Euclidean distances calculated along the columns and rows respectively.
20
50 20 10 5 2
Number of transcripts within BTRs
100
0.5
0.6
0.7
0.8
0.9
1.0
Median correlation within BTRs
S15 Fig. Characterization of BTRs. Scatterplot shows the distribution of BTRs based on their within-group similarity (median of pairwise correlations within a BTR), and number of transcripts within. Intensity of grey dots represents the number of overlapping points: the darker, the greater the number. Top and side histograms show the overall distribution of BTRs according to each variable.
21
Biological Processes Biological Processes
oligosaccharide metabolic process carbohydrate metabolic process response to oxidative stress response to chemical amino acid transport carbohydrate transport regulation of organelle organization cytoskeleton organization mitotic cell cycle protein dephosphorylation cell budding regulation of cell cycle regulation of translation nucleus organization cell morphogenesis sporulation cell wall organization or biogenesis nucleobase−containing compound transport cytoplasmic translation translational elongation tRNA aminoacylation for protein translation cellular amino acid metabolic process cellular ion homeostasis generation of precursor metabolites and energy cellular respiration DNA repair cellular response to DNA damage stimulus meiotic cell cycle organelle fission chromosome segregation regulation of protein modification process DNA−templated transcription, termination DNA−templated transcription, elongation DNA−templated transcription, initiation chromatin organization vitamin metabolic process cofactor metabolic process response to starvation organelle inheritance signaling conjugation protein phosphorylation cytokinesis protein modification by small protein conjugation or removal DNA replication telomere organization DNA recombination lipid transport endocytosis exocytosis organelle fusion membrane fusion Golgi vesicle transport protein acylation peptidyl−amino acid modification histone modification transposition invasive growth in response to glucose limitation regulation of transport nucleobase−containing small molecule metabolic process ion transport monocarboxylic acid metabolic process lipid metabolic process vacuole organization membrane invagination mitochondrion organization mitochondrial translation RNA splicing mRNA processing ribosome assembly organelle assembly nuclear transport ribosomal large subunit biogenesis rRNA processing ribosomal small subunit biogenesis RNA modification ribosomal subunit export from nucleus tRNA processing snoRNA processing transcription from RNA polymerase III promoter transcription from RNA polymerase I promoter translational initiation proteolysis involved in cellular protein catabolic process protein maturation protein complex biogenesis response to heat protein folding protein lipidation protein glycosylation transmembrane transport protein targeting pseudohyphal growth regulation of DNA metabolic process response to osmotic stress RNA catabolic process transcription from RNA polymerase II promoter vesicle organization
0.00
0.01
amino acid transport and metabolism carbohydrates transport and metabolism cell cycle cell polarity/morphogenesis DNA metabolic process
0.02
BTRs
translaAon transport
0.03
signaling/stress response small molecule transport and metabolism transcripAon
BTRs lipid transport and metabolism nucleobase transport and metabolism organelle organisaAon protein modificaAon RNA processing
0.04
0.05
22
1362 1229 1256 1203 1061 1240 958 1109 922 1369 919 967 1264 903 899 895 894 811 767 704 754 1104 653 876 568 554 760 1260 535 861 490 1318 486 649 1210 447 893 378 588 351 864 328 856 318 381 293 646 284 280 566 608 258 915 986 413 886 945 234 538 802 1001 341 857 1245 229 289 252 1204 222 810 1315 267 212 224 228 533 601 207 286 242 534 451 551 202 696 356 407 1010 200 264 487 536 191 443 188 477 763 380 276 209 183 192 411 1136 179 783 173 235 942 1176 160 206 629 156 734 676 406 402 201 310 150 182 215 230 146 587 282 336 376 410 135 791 110 285 187 102 417 148 271 951 909 585 389 495 565 90 371 479 396 375 352 247 279 111 219 333 470 331 347 180 141 60 214 1198 50 330 939 615 631 43 275 29 468 73 68 65 63 19 44 882 841 3 297
S16 Fig. Biological processes overrepresented within BTRs (whole heatmap). Red intensity represents the FDR value. Terms are grouped in 15 categories, and their name coloured accordingly. Zoomed in version of some areas of the heatmap in S13 Fig.
23
regulation of organelle organization
cellular respiration
generation of precursor metabolites and energy
0.05
0.04
BTRs
0.04
0.05 regulation of organelle organization
0.02
mitotic cell cycle
0.03 cytoskeleton organization 0.01 0.00
protein dephosphorylation cell budding DNA repair
regulation of cell cycle
cellular response to DNA damage stimulus meiotic cell cycle
1001 0.01
0.02
0.03
0.04
0.05
615 0.00
631
341
transport
translaAon
0.05
0.04
0.03
transcripAon
0.05
0.04
0.03
0.02
0.01
0.00
small molecule transport and metabolism
signaling/stress response
RNA processing
protein modificaAon
organelle organisaAon
nucleobase transport and metabolism
lipid transport and metabolism
DNA metabolic process
cell polarity/morphogenesis
cell cycle
carbohydrates transport and metabolism
amino acid transport and metabolism
0.00
0.01
0.02
857
regulation of translation
BTRs
802 939
organelle fission chromosome segregation
538
BTRs
330 60
234
cytoskeleton organization
0.05
141
50 180
0.03
0.04
BTRs
331
mitotic cell cycle
0.03
regulation of protein modification process
470
0.02
0.02
BTRs
ribosome assembly
nuclear transport
organelle assembly
rRNA processing ribosomal small subunit biogenesis RNA modification ribosomal subunit export from nucleus tRNA processing snoRNA processing
333
183 ribosomal large subunit biogenesis
Biological Processes
transcription from RNA polymerase I promoter
219
209 transcription from RNA polymerase III promoter
translational initiation
111
protein dephosphorylation
0.01
375
945 1198 347
0.01
396
cell budding
0.00
479
192
Biological Processes
276
Biological Processes 0.05 0.04 0.03 0.02 0.01 0.00
214
0.00
90
regulation of cell cycle
BTRs
oligosaccharide metabolic process carbohydrate metabolic process response to oxidative stress response to chemical amino acid transport carbohydrate transport regulation of organelle organization cytoskeleton organization mitotic cell cycle protein dephosphorylation cell budding regulation of cell cycle regulation of translation nucleus organization cell morphogenesis sporulation cell wall organization or biogenesis nucleobase−containing compound transport cytoplasmic translation translational elongation tRNA aminoacylation for protein translation cellular amino acid metabolic process cellular ion homeostasis generation of precursor metabolites and energy cellular respiration DNA repair cellular response to DNA damage stimulus meiotic cell cycle organelle fission chromosome segregation regulation of protein modification process DNA−templated transcription, termination DNA−templated transcription, elongation DNA−templated transcription, initiation chromatin organization vitamin metabolic process cofactor metabolic process response to starvation organelle inheritance signaling conjugation protein phosphorylation cytokinesis protein modification by small protein conjugation or removal DNA replication telomere organization DNA recombination lipid transport endocytosis exocytosis organelle fusion membrane fusion Golgi vesicle transport protein acylation peptidyl−amino acid modification histone modification transposition invasive growth in response to glucose limitation regulation of transport nucleobase−containing small molecule metabolic process ion transport monocarboxylic acid metabolic process lipid metabolic process vacuole organization membrane invagination mitochondrion organization mitochondrial translation RNA splicing mRNA processing ribosome assembly organelle assembly nuclear transport ribosomal large subunit biogenesis rRNA processing ribosomal small subunit biogenesis RNA modification ribosomal subunit export from nucleus tRNA processing snoRNA processing transcription from RNA polymerase III promoter transcription from RNA polymerase I promoter translational initiation proteolysis involved in cellular protein catabolic process protein maturation protein complex biogenesis response to heat protein folding protein lipidation protein glycosylation transmembrane transport protein targeting pseudohyphal growth regulation of DNA metabolic process response to osmotic stress RNA catabolic process transcription from RNA polymerase II promoter vesicle organization
585
763 279
0.05 0.04 0.03
247
regulation of translation
proteolysis involved in cellular protein catabolic process
protein maturation 0.02 0.01 0.00
371
BTRs
352
945 protein complex biogenesis
857 381
24
1001
341
BTRs
565
318
mitochondrion organization
389
380
1362 1229 1256 1203 1061 1240 958 1109 922 1369 919 967 1264 903 899 895 894 811 767 704 754 1104 653 876 568 554 760 1260 535 861 490 1318 486 649 1210 447 893 378 588 351 864 328 856 318 381 293 646 284 280 566 608 258 915 986 413 886 945 234 538 802 1001 341 857 1245 229 289 252 1204 222 810 1315 267 212 224 228 533 601 207 286 242 534 451 551 202 696 356 407 1010 200 264 487 536 191 443 188 477 763 380 276 209 183 192 411 1136 179 783 173 235 942 1176 160 206 629 156 734 676 406 402 201 310 150 182 215 230 146 587 282 336 376 410 135 791 110 285 187 102 417 148 271 951 909 585 389 495 565 90 371 479 396 375 352 247 279 111 219 333 470 331 347 180 141 60 214 1198 50 330 939 615 631 43 275 29 468 73 68 65 63 19 44 882 841 3 297
495
538 mitochondrial translation
909
802 856
Biological Processes Biological Processes
951
234
Biological Processes
Biological Processes Biological Processes
S17 Fig. Biological processes overrepresented within BTRs (zoomed in). Details of BTRs participating in similar biological processes. Red intensity represents the FDR value. Terms are grouped in 15 categories, and their name coloured accordingly.
25
B
0
0.6 0.0
0.2
0.4
Proportion
40 20
Frequency
60
0.8
80
A
1
2
3
4
5
6+
0
D
3
4
5
6+
0.4 0.3
Proportion
0.0
0.0
0.1
0.2
0.6 0.4 0.2
Proportion
2
Number of GIs per BTR
0.8
C
1
0.5
Number of significant Biological Processes per BTR
0
1
2
3
4
Number of PPIs per BTR
5
6+
2
3
4
5
6+
Number of transcripts per BTR
S18 Fig. Functional similarity within BTRs. A Number of GO Slim Biological Processes that are significantly enriched within each BTR. B. Number of significant (dark grey) and non- significant (light grey) genetic interactions within BTR. C. Number of significant (dark grey) and non-significant (light grey) protein-protein interactions within BTR. D. Number of transcripts per BTR for BTRs having a significant enrichment in A-C (dark grey) or not having any enrichment in A-C (light grey).
26
100
1000 1 2
100
1
10
100
0.8 0.6
Proportion of possible PPIs/BTR
0.0 2
Number of genes/BTR
100
1.0
1.0 0.8 0.6 0.4
Proportion of possible PPIs/BTR
0.0 2
10
Number of GIs/BTR
0.2
1.0 0.8 0.6 0.4 0.2 0.0
Proportion of possible GIs/BTR
10
Number of genes/BTR
0.4
10
Number of genes/BTR
0.2
2
100
Number of PPIs/BTR
100 10
Number of PPIs/BTR
1000
C
1
10 1
Number of GIs/BTR
100
B
10
A
10
Number of genes/BTR
100
0.0
0.2
0.4
0.6
0.8
1.0
Proportion of possible GIs/BTR
S19 Fig. Significance of interactions within BTRs. Number of (and proportion of all possible) genetic (A) and physical (B) interactions per BTR compared to the size of BTR. Significant cases are shown in red. Random expectation was calculated through a resampling process, and is shown as a grey shade (90% confidence intervals for the expectation). C. Number of (and proportion of all possible) physical and genetic interactions within BTRs. BTRs may have a significant overrepresentation of physical (green), genetic (blue) or both interactions (red). BTRs with no overrepresentation are shown in grey. Significance was established as p-value < 0.05. The intensity of the colour is proportional to the number of cases represented by a single point.
27
500 400 0
0
100
100
200
300
Frequency
300 200
Frequency
600
500
B
400
A
0.0
0.2
0.4
0.6
Jaccard Index Median
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
Jaccard Index Median
S20 Fig. Regulation of transcription within and between BTRs. Histograms show the distribution of overlapping sets of transcription factors involved in regulating the expression of transcripts measured as the median of Jaccard Indices (number of TFs controlling the expression of both genes/number of TFs controlling the expression of either of the genes). The grey shades show the expected tip of the histogram bars calculated using resampling. A. Within BTRs. B. Between BTRs.
28
Top 1%
Top 5%
Top 10%
Neither top nor bottom
Bottom 10%
Bottom 5%
Bottom 1%
20 81 24 83 29 36 55 92 82 59 60 44 87 10 145 43 101 98 21 158 129 28 46 119 45 91 114 122 149 104 160 47 50 76 34 120 166 22 100 86 65 80 163 18 139 16 74 102 194 23 40 93 54 38 72 115 52 26 63 131 117 209 25 71 128 51 32 112 69 77 183 155 110 130
381 318 535 204 215 160 168 206 228 149 113 43 371 396 90 565 99 258 209 183 596 337 268 115 214 141 111 60 341 330 487 384 272 38 166 10 263 157 202 244 242 170 176 338 231 29 327 261 373 323 86 80 49 40 26 13 18 82 73 68 4 23 348 54 187 50 25 9 42 28 11 12 46 6 7 635 143 98 97 78 275 285 180 173 108 92
S21 Fig. BTRs suffering extreme expression changes. Heatmap shows if more than half of the members of a specific BTR are in one of the subsets of great changes of a particular PSR. Red shows membership of the subsets of induced RNAs, whereas blue shows membership of the subsets of repressed RNAs. The brighter the colour, the more extreme the percentile. PSRs and BTRs are ordered as they are in Fig 8: PSRs in columns, BTRs in rows. Grey squares show when there was no data available. Black lines divide the heatmap in the different global responses and response layers shown in Fig 8.
29
MDS for all experiments 0.6
●
●
0.2
oxidative stress
● ●
● ● ●
●
amino acid starvation
●
0.0
BCV distance 2
0.4
●
● ●
−0.2
control
−0.4
glucose starvation
−0.5
0.0
0.5
1.0
BCV distance 1 S22 Fig. Multi-dimensional scaling of transcriptomes from yeast grown
under different stress conditions. Control (red); amino acid starvation (green); glucose starvation (blue); and, oxidative stress (purple). The point shapes represent the tags used in the experiment: eIF4E (squares); eIF4G1 (triangles); and, eIF4G2 (circles). It demonstrates that transcriptomes cluster because of stress instead of tag.
30
Similarity of transcriptome response to stress
0
5 10
Count
Key+Histo
0
0.2
0.4
Distance eIF4G2 +H2O2 eIF4G1 +H2O2 eIF4E +H2O2 eIF4E −D eIF4G2 −D eIF4G1 −D eIF4G2 −AA eIF4E −AA
eIF4G2 +H2O2
eIF4G1 +H2O2
eIF4E +H2O2
eIF4E −D
eIF4G2 −D
eIF4G1 −D
eIF4G2 −AA
eIF4E −AA
eIF4G1 −AA
eIF4G1 −AA
S23 Fig. Similarity of transcriptional response to stress (stress vs. control). It demonstrates that stress responses cluster because of stress instead of tag.
31
Intersection of up−regulated genes
−D
−AA
97 1255
80 45
138
40 104
Intersection of down−regulated genes
Intersection of no−change genes
−D
−AA
+H2 O2
−D
−AA
40 1264
128 179
93
58 65
237 2365
106
128
2301
87
239
+H2 O2
+H2 O2
S24 Fig. Common stress responses. Overlapping sets of up-regulated genes (A), down- regulated genes (B), and genes with no statistical change (C) following 3 different stresses: amino acid starvation, glucose starvation, and oxidative stress. Statistical significance set at FDR 1%.
32
1000 1500 2000 2500 0
500
Frequency
−AA
−7
−6
−5
−4
−3
−2
−1
0
1
2
3
4
5
6
7
8
9
2
3
4
5
6
7
8
9
2
3
4
5
6
7
8
9
log2 FC
1000 1500 2000 2500 0
500
Frequency
−D
−7
−6
−5
−4
−3
−2
−1
0
1
log2 FC
1000 1500 2000 2500 0
500
Frequency
+H2 O2
−7
−6
−5
−4
−3
−2
−1
0
1
log2 FC
S25 Fig. Magnitude of transcriptional stress-response. Histograms show the distribution of log2 fold-changes. Significant differentially-expressed transcripts are shown in red, the rest are shown in black.
33
−AA
−D
+H2O2 Enriched
monocarboxylic acid metabolic process carbohydrate metabolic process ion transport cellular amino acid metabolic process amino acid transport endosomal transport cellular respiration response to starvation peroxisome organization protein phosphorylation protein maturation membrane invagination generation of precursor metabolites and energy response to oxidative stress response to chemical nucleobase−containing small molecule metabolic process
amino acid transport and metabolism carbohydrates transport and metabolism cell cycle
lipid metabolic process cellular ion homeostasis
Biological Processes
transmembrane transport cofactor metabolic process carbohydrate transport protein lipidation mitochondrion organization invasive growth in response to glucose limitation cell wall organization or biogenesis chromatin organization
No change
nucleus organization Golgi vesicle transport RNA catabolic process protein glycosylation peptidyl−amino acid modification protein targeting DNA−templated transcription, initiation
cell polarity/morphogenesis DNA metabolic process lipid transport and metabolism nucleobase transport and metabolism organelle organisaAon protein modificaAon RNA processing signaling/stress response small molecule transport and metabolism transcripAon translaAon transport
DNA−templated transcription, termination response to heat translational initiation transcription from RNA polymerase III promoter snoRNA processing regulation of translation nucleobase−containing compound transport tRNA aminoacylation for protein translation protein folding ribosomal small subunit biogenesis ribosomal large subunit biogenesis ribosome assembly rRNA processing organelle assembly
Enriched
ribosomal subunit export from nucleus nuclear transport RNA modification
No change
transcription from RNA polymerase I promoter cytoplasmic translation
Depleted Depleted All 2x 4x 8x All 2x 4x 8x All 2x 4x 8x
tRNA processing
Transcript variation
S26 Fig. Biological processes affected by stress response. GO Slim terms are that are overrepresented in the set significantly-enriched transcripts (red), the set of significantly-depleted transcripts (blue), or in both sets (black). Terms are grouped in 15 categories, and their name coloured accordingly.
34
MRD1 BUD27
ENP2 NOP53
RPC82
TSR2 TRZ1 UTP14
DBP7
BMT6 NRP1 CMS1
ATC1 YGR160W
NOP4
SSF2
RRP17
SUA5
BCP1 BAS1 MAK16
NUC1
STB5
SLX9 URK1 EFG1
FAL1
ROK1
YML082W
TRM13 BUD22
YCR016W JJJ1
OGG1 NOP12
BFR2 SPB4
PUF6
LTV1
POL1 YOX1YHP1
POL12 CDC9
SPB1
GRC3
YNL120C YHR218W
UTP30
NOP9
BMT5 YFL065C UTP4
SMC3 IRR1
PDS5 TMA16 ACM1 YEL075C MBP1
IPI3
CDC45
CLN1
ESF2
RAD27
GIN4
FAF1
NOP7
CLB6 RCL1
YPR203W
MCD1 YFL064C YLR463C SPT21 YLR464W YPR202W SYO1 YEL076C YLR462WYHL049CCDC21 TOS4 YER189W YBL111C SWI4
SWI6
YAP5
CTF18 POL30
S27 Fig. Use of BTRs for functional annotation. Network of transcription factors associated with BTRs 60 (pink), 263 (yellow), and 330 (green); transcription factors shown as diamonds.
35