Genome-wide identification of post-translational modulators of transcription factor activity in human B cells.
The ability of a transcription factor (TF) to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms, resulting in highly context-dependent regulatory networks. However, high-throughput methods for the identification of proteins that affect TF activity are still largely unavailable. Here we introduce an algorithm, modulator inference by network dynamics (MINDy), for the genome-wide identification of post-translational modulators of TF activity within a specific cellular context. When used to dissect the regulation of MYC activity in human B lymphocytes, the approach inferred novel modulators of MYC function, which act by distinct mechanisms, including protein turnover, transcription complex formation and selective enzyme recruitment. MINDy is generally applicable to study the post-translational modulation of mammalian TFs in any cellular context. As such it can be used to dissect context-specific signaling pathways and combinatorial transcriptional regulation.
Wang
Kai
K
Department of Biomedical Informatics, Columbia University, New York, New York, USA.
Saito
Masumichi
M
Bisikirska
Brygida C
BC
Alvarez
Mariano J
MJ
Lim
Wei Keat
WK
Rajbhandari
Presha
P
Shen
Qiong
Q
Nemenman
Ilya
I
Basso
Katia
K
Margolin
Adam A
AA
Klein
Ulf
U
Dalla-Favera
Riccardo
R
Califano
Andrea
A
D000465:Algorithms; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D046228:Microarray Analysis; D008957:Models, Genetic; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D056284:Histone Deacetylase 1; D018398:Homeodomain Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C107989:BHLHE40 protein, human; C578038:MEF2B protein, human; C491614:STK38 protein, human; C110550:HDAC1 protein, human