Supplementary information


Overview
  1. Module 1
  2. Module 2
  3. Module 3
  4. Module 4
  5. Module 5
  6. Module 6
  7. References
An overview of the modules involved in the cell cycle is given in the Figure below. Cell cycle dependency of the identified modules was identified by their seed profiles showing an oscillating behavior and the overrepresented functional classes in the respective modules being related to cell cycle. For each module the corresponding expression profile is indicated in the same color (e.g. red profile belongs to module 1 (Mbp1, Swi4, Swi6, Stb1). These different modules are known to be essential at the different phases of the cell cycle as indicated by the bar. This is also illustrated by the shifted peaking of their different profiles.

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Parameters used

An overview of the parameters used to infer the regulatory modules is given in the table below. +: module detected, /: module not detected


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Module 1

Genes and Motifs

Genes Mbp1, Swi4, Swi6, Stb1
Motifs M_18 (Mbp1), M_12(Mbp1), M_11 (Swi4), M_67(Swi4)

p-values

Seed profile p-value ChIP p-value Motif

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Functional Overrepresentation


Detected Genes
Gene Name AccessionNr Description
YDL003W MCD1 NC_001136 YDL003W Mcd1p Mitotic Chromosome Determinant; similar to S. pombe RAD21; may function in chromosome morphogenesis from S phase through mitosis
YER001W MNN1 NC_001137 YER001W Mnn1p Alpha-1,3-mannosyltransferase
YGR109C CLB6 NC_001139 YGR109C Clb6p role in DNA replication during S phase
YGR189C CRH1 NC_001139 YGR189C Crh1p congo red hypersensitive
YGR221C TOS2 NC_001139 YGR221C Tos2p Hypothetical ORF
YHR149C YHR149C NC_001140 Yhr149cp Hypothetical ORF
YER070W RNR1 NC_001137 YER070W Rnr1p ribonucleotide reductase
YPL256C CLN2 NC_001148 YPL256C Cln2p role in cell cycle START
YNL300W TOS6 NC_001146 YNL300W Tos6p Hypothetical ORF
YPL163C SVS1 NC_001148 YPL163C Svs1p involved in vanadate resistance
YPL267W YPL267W NC_001148 Ypl267wp Hypothetical ORF
YPR120C CLB5 NC_001148 YPR120C Clb5p role in DNA replication during S phase; additional functional role in formation of mitotic spindles along with Clb3 and Clb4
YMR199W CLN1 NC_001145 YMR199W Cln1p role in cell cycle START
YMR179W SPT21 NC_001145 YMR179W Spt21p involved in trascriptional regulation of Ty1 LTRs
YML027W YOX1 NC_001145 YML027W Yox1p Homeodomain protein that binds leu-tRNA gene
YKL113C RAD27 NC_001143 YKL113C Rad27p DNA repair protein that belongs to the RAD2(pombe)*FEN1 subfamily

Correlation between genes

66 genes were correlated with the seed profile (minimal correlation of 0.7). In 18 of the 66 genes, the complete module consisting of all 4 motifs and 4 regulators was present (Table 2). Based on the functional categories that were significantly overrepresented in this subset of 18 genes, this module was clearly involved in cell cycle, DNA synthesis and replication. Note that if the complete module (consisting of all regulators with their respective putative motifs) would be responsible for the observed expression pattern, a large overlap between the genes recruited using the stringent conditions (presence of all regulators and motifs) versus the recruitment based on the correlation only is to be expected. This not being the case (in this example we only recovered 18 genes of the 66) can, to some extent, be explained by the presence of a large number of false negative measurements in the respective datasets. Alternatively the large module consisting of 4 regulators might only be present in a subset of genes correlated with the seed profile (in 18 genes in this case). The other 48 genes might contain different combinations of the same subset of regulators and motifs. Indeed we also found strong evidence for the presence of modules containing regulator combinations (Swi4, Swi6), (Mbp1, Swi4), (Mbp1, Swi6), (Stb1, Swi4) and (Mbp1, Swi4, Swi6). Therefore, we verified which combination of regulators occurred most frequently in this set of 66 genes, correlated with the seed profile. These appeared to be the combination (Mbp1, Swi4, Swi6, Stb1) and (Mbp1, Swi6). Therefore, we could hypothesize that a subset of the genes with a profile correlated to the seed profile (18) are regulated by all 4 regulators, for other genes the presence of only 2 or 3 regulators would be sufficient. These detected dependencies seemed to be biologically relevant as it is known that SBF and MBF are both heteromeric transcription factors that are involved in the transcriptional activation during G1. Both regulators share a common regulatory subunit Swi6 that is tethered to DNA via its binding partners Swi4 and Mbp1 in SBF and MBF respectively. The distinction between SBF and MBF mediated transcriptional control is not absolute and partially redundant as Mbp1 and Swi4 would share 34% of their target genes.

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Module 2

Genes and Motifs

Genes Mbp1, Swi4, Swi6, Fkh2
Motifs M_18 (Mbp1), M_12(Mbp1), M_11 (Swi4), M_8(Mcm)

p-values

Seed profile p-value ChIP p-value Motif

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Functional Overrepresentation


Results for different parameters

Detected Genes
Gene Name AccessionNr Description
YDL003W MCD1 NC_001136 YDL003W Mcd1p Mitotic Chromosome Determinant; similar to S. pombe RAD21; may function in chromosome morphogenesis from S phase through mitosis
YGR143W SKN1 NC_001139 YGR143W Skn1p Involved in (1->6)-beta-glucan biosynthesis
YIL123W SIM1 NC_001141 YIL123W Sim1p (putative) invovled in control of DNA replication
YHR061C GIC1 NC_001140 YHR061C Gic1p Gtpase-interacting component 1
YDR451C YHP1 NC_001136 YDR451C Yhp1p
YBR078W ECM33 NC_001134 YBR078W Ecm33p ExtraCellular Mutant
YDR261C EXG2 NC_001136 YDR261C Exg2p Exo-1,3-b-glucanase
YJL080C SCP160 NC_001142 YJL080C Scp160p May be required during cell division for faithful partitioning of the ER-nuclear envelope membranes, involved in control of mitotic chromsome transmission
YLR300W EXG1 NC_001144 YLR300W Exg1p Exo-1,3-beta-glucanase
YLR380W CSR1 NC_001144 YLR380W Csr1p chs5 spa2 rescue; isolated as a multicopy suppressor of the lethality of chs5 spa2 double mutant at 37 degrees.
YLR342W FKS1 NC_001144 YLR342W Fks1p Required for viability of calcineurin mutants
YLR437C YLR437C NC_001144 Ylr437cp Hypothetical ORF
YOR114W YOR114W NC_001147 Yor114wp Hypothetical ORF
YPL127C HHO1 NC_001148 YPL127C Hho1p Histone H1
YNL089C YNL089C NC_001146 Ynl089cp Hypothetical ORF
YJL187C SWE1 NC_001142 YJL187C Swe1p protein kinase homolog
YNR009W YNR009W NC_001146 Ynr009wp Hypothetical ORF
YPL163C SVS1 NC_001148 YPL163C Svs1p involved in vanadate resistance
YMR199W CLN1 NC_001145 YMR199W Cln1p role in cell cycle START
YMR215W YMR215W NC_001145 Ymr215wp Hypothetical ORF
YJL186W MNN5 NC_001142 YJL186W Mnn5p mannan synthesis
YOR247W SRL1 NC_001147 YOR247W Srl1p Suppressor of rad53 lethality
YNL238W KEX2 NC_001146 YNL238W Kex2p prohormone processing; golgi localization marker, dispensable for meiotic recombination but partially required for meiosis I and*or meiosis II
YLR056W ERG3 NC_001144 YLR056W Erg3p C-5 sterol desaturase
YJL092W HPR5 NC_001142 YJL092W Hpr5p Required for proper timing of committment to meiotic recombination and the transition from Meiosis I to Meiosis II
YKL096W CWP1 NC_001143 YKL096W Cwp1p cell wall protein, involved in O and N glycosylation, acceptor of B1-6 glucan.
YLR297W YLR297W NC_001144 Ylr297wp Hypothetical ORF
YML027W YOX1 NC_001145 YML027W Yox1p Homeodomain protein that binds leu-tRNA gene
YJL158C CIS3 NC_001142 YJL158C Cis3p cik1 suppressor
Correlation between genes

Mbp1 Swi6 Swi4 Stb1
Mbp1 0      
Swi6 1.0068E-06 0    
Swi4 0.2532 0.0513 0  
Stb1 0.2029 0.273 0.0033 0

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Module 3

Genes and Motifs

Genes NDD1, FKH2, Mcm1
Motifs M_8 (Mcm1), M_30(Mcm1)

p-values

Seed profile p-value ChIP p-value Motif

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Functional Overrepresentation


Results for different parameters

Detected Genes
Gene Name AccessionNr Description
YDR033W MRH1 NC_001136 YDR033W Mrh1p Membrane protein related to Hsp30p; Localized by immunofluorescence to membranes, mainly the plasma membr. punctuate immunofluorescence pattern observed in buds. The nuclear envelope, but not vacuole or mitochondrial membranes also stained
YAR018C KIN3 NC_001133 YAR018C Kin3p protein kinase
YDR146C SWI5 NC_001136 YDR146C Swi5p transcriptional activator
YIL158W YIL158W NC_001141 Yil158wp Hypothetical ORF
YGL116W CDC20 NC_001139 YGL116W Cdc20p Required for onset of anaphase
YJL051W YJL051W NC_001142 Yjl051wp Hypothetical ORF
YGL021W ALK1 NC_001139 YGL021W Alk1p
YGR143W SKN1 NC_001139 YGR143W Skn1p Involved in (1->6)-beta-glucan biosynthesis
YHR023W MYO1 NC_001140 YHR023W Myo1p myosin class II
YBR038W CHS2 NC_001134 YBR038W Chs2p chitin synthase 2
YCR024C-A PMP1 NC_001135 YCR024C-A Pmp1p May regulate plasma membrane H(+)-ATPase
YLR084C RAX2 NC_001144 YLR084C Rax2p Involved in the maintenance of bipolar pattern
YMR001C CDC5 NC_001145 YMR001C Cdc5p CDC5 is dispensable for premeiotic DNA synthesis and recombination, but required for tripartite synaptonemal complexes, haploidization, and spores
YML119W YML119W NC_001145 Yml119wp Hypothetical ORF
YLR190W YLR190W NC_001144 Ylr190wp Hypothetical ORF
YPR119W CLB2 NC_001148 YPR119W Clb2p Involved in mitotic induction
YPL141C YPL141C NC_001148 Ypl141cp Hypothetical ORF
YJR092W BUD4 NC_001142 YJR092W Bud4p co-assembles with Bud3p at bud sites
YLR131C ACE2 NC_001144 YLR131C Ace2p involved in transcriptional regulation of CUP1

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Module 4

Genes and Motifs

Genes Swi5 (ace2)
Motifs M_8 (Mcm1)

p-values

Seed profile p-value ChIP p-value Motif

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Functional Overrepresentation


Results for different parameters

Detected Genes
Gene Name AccessionNr Description
YIL009W FAA3 NC_001141 YIL009W Faa3p acyl-CoA synthetase (long-chain fatty acid CoA ligase) (fatty acid activator 3), activates endogenous but not imported fatty acids and provides substrates for N-myristoylation
YDL117W CYK3 NC_001136 YDL117W Cyk3p involved in CYtoKinesis
YDR055W PST1 NC_001136 YDR055W Pst1p Protoplasts-secreted
YJL159W HSP150 NC_001142 YJL159W Hsp150p Heat shock protein, secretory glycoprotein
YKL163W PIR3 NC_001143 YKL163W Pir3p Protein containing tandem internal repeats
YKL164C PIR1 NC_001143 YKL164C Pir1p Protein containing tandem internal repeats
YNL327W EGT2 NC_001146 YNL327W Egt2p cell-cycle regulation protein, may be involved in the correct timing of cell separation after cytokinesis
YOR066W YOR066W NC_001147 Yor066wp Hypothetical ORF
YNL078W JIP1 NC_001146 YNL078W Jip1p Hypothetical ORF
YKL185W ASH1 NC_001143 YKL185W Ash1p Zinc-finger inhibitor of HO transcription which is asymmetrically localized to the daughter cell nucleus

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Module 5

Genes and Motifs

Genes FKL1, Yap5, Rap1
Motifs M_54

p-values

Seed profile p-value ChIP p-value Motif

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Functional Overrepresentation


Results for different parameters

Detected Genes
Gene Name AccessionNr Description
YDL136W RPL35B NC_001136 YDL136W Rpl35bp Homology to rat L35
YDL130W RPP1B NC_001136 YDL130W Rpp1bp Homology to rat P1, human P1, and E. coli L12eIIB
YDL083C RPS16B NC_001136 YDL083C Rps16bp Homology to rat S16
YGR148C RPL24B NC_001139 YGR148C Rpl24bp Homology to rat L24
YDR450W RPS18A NC_001136 YDR450W Rps18ap Homology to rat S18 and E. coli S13
YGL189C RPS26A NC_001139 YGL189C Rps26ap Homology to rat S26
YER056C-A RPL34A NC_001137 YER056C-A Rpl34ap Homology to rat L34
YER131W RPS26B NC_001137 YER131W Rps26bp Homology to rat S26
YGL031C RPL24A NC_001139 YGL031C Rpl24ap Homology to rat L24
YGL103W RPL28 NC_001139 YGL103W Rpl28p Homology to rat, mouse L27a
YER102W RPS8B NC_001137 YER102W Rps8bp Homology to mammalian S8
YBL072C RPS8A NC_001134 YBL072C Rps8ap Homology to mammalian S8
YCR031C RPS14A NC_001135 YCR031C Rps14ap Homology to mammalian S14, E. coli S11
YBR118W TEF2 NC_001134 YBR118W Tef2p translational elongation factor EF-1 alpha
YBR189W RPS9B NC_001134 YBR189W Rps9bp Homology to rat S9 and E. coli S4
YLR167W RPS31 NC_001144 YLR167W Rps31p Homology to rat S27a
YLR061W RPL22A NC_001144 YLR061W Rpl22ap Homology to rat L22
YLR333C RPS25B NC_001144 YLR333C Rps25bp Homology to rat S25; belongs to the S25E family of ribosomal proteins
YOL127W RPL25 NC_001147 YOL127W Rpl25p Homology to E. coli L23 and rat L23a
YOL040C RPS15 NC_001147 YOL040C Rps15p Homology to rat S15 and E. coli S19
YOR293W RPS10A NC_001147 YOR293W Rps10ap Homology to rat S10
YPL090C RPS6A NC_001148 YPL090C Rps6ap Homology to rat, mouse, and human S6
YPL220W RPL1A NC_001148 YPL220W Rpl1ap Homology to rat L10a, eubacterial L1, and archaebacterial L1; identical to S. cerevisiae L1B (Ssm2p)
YOR096W RPS7A NC_001147 YOR096W Rps7ap Homology to human S7 and Xenopus S8
YLR344W RPL26A NC_001144 YLR344W Rpl26ap Homology to rat L26
YLR441C RPS1A NC_001144 YLR441C Rps1ap Homologous to rat S3A
Module 6

Genes and Motifs

Genes /
Motifs ESR1, ESR2

p-values

Seed profile p-value ChIP p-value Motif

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Functional Overrepresentation


Results for different parameters

Detected Genes
Gene Name AccessionNr Description
YCR057C PWP2 NC_001135 YCR057C Pwp2p Eight WD-repeats with homology with G protein beta subunits flanked by nonhomologous N-terminal and C-terminal extensions
YCR091W KIN82 NC_001135 YCR091W Kin82p Putative serine*threonine protein kinase most similar to cyclic nucleotide-dependent protein kinase subfamily and the protein kinase C subfamily
YDR184C ATC1 NC_001136 YDR184C Atc1p interacts with AIP3, localized to the nucleus
YAL025C MAK16 NC_001133 YAL025C Mak16p putative nuclear protein
YDR083W RRP8 NC_001136 YDR083W Rrp8p
YDR449C YDR449C NC_001136 Ydr449cp Protein required for cell viability
YER127W LCP5 NC_001137 YER127W Lcp5p Lethal with conditional pap1 allele
YGL099W KRE35 NC_001139 YGL099W Kre35p Killer toxin REsistant
YGL171W ROK1 NC_001139 YGL171W Rok1p contains domains found in the DEAD protein family of ATP-dependent RNA helicases; high-copy suppressor of kem1 null mutant
YHR196W YHR196W NC_001140 Yhr196wp Protein required for cell viability
YIL103W YIL103W NC_001141 Yil103wp Hypothetical ORF
YIL127C YIL127C NC_001141 Yil127cp Hypothetical ORF
YHR065C RRP3 NC_001140 YHR065C Rrp3p Required for maturation of the 35S primary transcript of pre-rRNA and is required for cleavages leading to mature 18S RNA
YGR128C YGR128C NC_001139 Ygr128cp Protein required for cell viability
YBR155W CNS1 NC_001134 YBR155W Cns1p cyclophilin seven suppressor
YGL120C PRP43 NC_001139 YGL120C Prp43p Pre-mRNA processing factor involved in disassembly of spliceosomes after the release of mature mRNA
YGR145W YGR145W NC_001139 Ygr145wp Protein required for cell viability
YIL091C YIL091C NC_001141 Yil091cp Protein required for cell viability
YER006W NUG1 NC_001137 YER006W Nug1p NUclear GTPase
YCR016W YCR016W NC_001135 Ycr016wp Hypothetical ORF
YER126C NSA2 NC_001137 YER126C Nsa2p Killer toxin Resistant; Nop seven associated protein 2
YHR085W YHR085W NC_001140 Yhr085wp Protein required for cell viability
YAL059W ECM1 NC_001133 YAL059W Ecm1p putative transmembrane domain protein involved in cell wall biogenesis
YCL054W SPB1 NC_001135 YCL054W Spb1p Suppressor of PaB1 mutant; involved in 60S ribosomal subunit biogenesis
YDR165W YDR165W NC_001136 Ydr165wp Hypothetical ORF
YCR072C YCR072C NC_001135 Ycr072cp Protein required for cell viability
YKR025W RPC37 NC_001143 YKR025W Rpc37p RNA Polymerase C (III) 37 kDa subunit; interacts with C53 subunit. C37 is an RNA polymerase III specific subunit.
YKR081C RPF2 NC_001143 YKR081C Rpf2p Hypothetical ORF
YLR196W PWP1 NC_001144 YLR196W Pwp1p Protein with periodic trytophan residues that resembles members of beta-transducin superfamily because of presence of WD-40 repeats
YKL099C YKL099C NC_001143 Ykl099cp Protein required for cell viability
YLR197W SIK1 NC_001144 YLR197W Sik1p homology to microtubule binding proteins and to X90565_5.cds
YMR049C ERB1 NC_001145 YMR049C Erb1p Eukaryotic Ribosome Biogenesis
YKL172W EBP2 NC_001143 YKL172W Ebp2p EBNA1-binding protein homolog
YOR001W RRP6 NC_001147 YOR001W Rrp6p Ribosomal RNA Processing
YML093W YML093W NC_001145 Yml093wp Protein required for cell viability
YNL248C RPA49 NC_001146 YNL248C Rpa49p 49-kDa alpha subunit of RNA polymerase A
YOL144W NOP8 NC_001147 YOL144W Nop8p Nucleolar protein required for 60S ribosome biogenesis
YNR046W YNR046W NC_001146 Ynr046wp Protein required for cell viability
YOL041C NOP12 NC_001147 YOL041C Nop12p Nucleolar Protein; isolated as a mutant exhibiting synthetic lethality with a nop2 ts allele.
YOR091W YOR091W NC_001147 Yor091wp Hypothetical ORF
YPL217C BMS1 NC_001148 YPL217C Bms1p BMH1 sensitive
YMR269W YMR269W NC_001145 Ymr269wp protein possibly involved in protein synthesis
YOR277C YOR277C NC_001147 Yor277cp Hypothetical ORF
YOR340C RPA43 NC_001147 YOR340C Rpa43p DNA-dependent RNA polymerase I subunit A43
YNL132W KRE33 NC_001146 YNL132W Kre33p Killer toxin REsistant
YOR206W NOC2 NC_001147 YOR206W Noc2p NucleOlar Complex 2; involved in nuclear export of pre-ribosomes
YPL211W NIP7 NC_001148 YPL211W Nip7p Nip7p is required for 60S ribosome subunit biogenesis
YNL061W NOP2 NC_001146 YNL061W Nop2p May participate in nucleolar function during the transition from stationary phase to rapid growth
YNL110C NOP15 NC_001146 YNL110C Nop15p Nucleolar protein 15
YJR002W MPP10 NC_001142 YJR002W Mpp10p Protein component of the U3 small nucleolar ribonucleoprotein (snoRNP)
YMR128W ECM16 NC_001145 YMR128W Ecm16p ExtraCellular Mutant
YLR129W DIP2 NC_001144 YLR129W Dip2p DOM34 Interacting Protein
YMR014W BUD22 NC_001145 YMR014W Bud22p
YJL109C YJL109C NC_001142 Yjl109cp Protein required for cell viability
YKL144C RPC25 NC_001143 YKL144C Rpc25p Subunit of RNA polymerase III
YLR074C BUD20 NC_001144 YLR074C Bud20p
YLR449W FPR4 NC_001144 YLR449W Fpr4p Homolog of homolog of the nucleolar FKBP, Fpr3
YKL082C YKL082C NC_001143 Ykl082cp Protein required for cell viability
YKR024C DBP7 NC_001143 YKR024C Dbp7p Dead-box protein
YLR051C YLR051C NC_001144 Ylr051cp Protein required for cell viability

Motif Logos


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Motif logos of the motifs correlated with the detected motifs.
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