TY - JOUR
T1 - Bayesian identification of candidate transcription factors for the regulation of Aqp2 gene expression
AU - Kikuchi, Hiroaki
AU - Jung, Hyun Jun
AU - Raghuram, Viswanathan
AU - Leo, Kirby T.
AU - Park, Euijung
AU - Yang, Chin Rang
AU - Chou, Chun Lin
AU - Chen, Lihe
AU - Knepper, Mark A.
N1 - Publisher Copyright:
© 2021 American Physiological Society. All rights reserved.
PY - 2021/9
Y1 - 2021/9
N2 - Aquaporin-2 (Aqp2) gene transcription is strongly regulated by vasopressin in the renal collecting duct. However, the transcription factors (TFs) responsible for the regulation of expression of Aqp2 remain largely unknown. We used Bayes theorem to integrate several-omics data sets to stratify the 1,344 TFs present in the mouse genome with regard to probabilities of regulating Aqp2 gene transcription. Also, we carried out new RNA sequencing experiments mapping the time course of vasopressininduced changes in the transcriptome of mpkCCD cells to identify TFs that change in tandem with Aqp2. The analysis identified 17 of 1,344 TFs that are most likely to be involved in the regulation of Aqp2 gene transcription. These TFs included eight that have been proposed in prior studies to play a role in Aqp2 regulation, viz., Cebpb, Elf1, Elf3, Ets1, Jun, Junb, Nfkb1, and Sp1. The remaining nine represent new candidates for future studies (Atf1, Irf3, Klf5, Klf6, Mef2d, Nfyb, Nr2f6, Stat3, and Nr4a1). Conspicuously absent is CREB (Creb1), which has been widely proposed to mediate vasopressin-induced regulation of Aqp2 gene transcription (Nielsen S, Frokiaer J, Marples D, Kwon TH, Agre P, Knepper MA. Physiol Rev 82: 205 244, 2002; Kortenoeven ML, Fenton RA. Biochim Biophys Acta 1840: 1533 1549, 2014; Bockenhauer D, Bichet DG. Nat Rev Nephrol 11: 576 588, 2015; Pearce D, Soundararajan R, Trimpert C, Kashlan OB, Deen PM, Kohan DE. Clin J Am Soc Nephrol 10: 135 146, 2015). Instead, another CREB-like TF, Atf1, ranked fourth among all TFs. RNA sequencing time-course experiments showed a rapid increase in Aqp2 mRNA, within 3 h of vasopressin exposure. This response was matched by an equally rapid increase in the abundance of the mRNA coding for Cebpb, which we have shown by chromatin immunoprecipitation-sequencing studies to bind downstream from the Aqp2 gene. The identified TFs provide a roadmap for future studies to understand regulation of Aqp2 gene expression. NEW & NOTEWORTHY Abetted by the advent of systems biology-based ("-omics") techniques in the 21st century, there has been a massive expansion of published data relevant to virtually every physiological question. The authors have developed a large-scale data integration approach based on the application of Bayes ' theorem. In the current work, they integrated 12 different-omics data sets to identify the transcription factors most likely to mediate vasopressin-dependent regulation of transcription of the aquaporin-2 gene.
AB - Aquaporin-2 (Aqp2) gene transcription is strongly regulated by vasopressin in the renal collecting duct. However, the transcription factors (TFs) responsible for the regulation of expression of Aqp2 remain largely unknown. We used Bayes theorem to integrate several-omics data sets to stratify the 1,344 TFs present in the mouse genome with regard to probabilities of regulating Aqp2 gene transcription. Also, we carried out new RNA sequencing experiments mapping the time course of vasopressininduced changes in the transcriptome of mpkCCD cells to identify TFs that change in tandem with Aqp2. The analysis identified 17 of 1,344 TFs that are most likely to be involved in the regulation of Aqp2 gene transcription. These TFs included eight that have been proposed in prior studies to play a role in Aqp2 regulation, viz., Cebpb, Elf1, Elf3, Ets1, Jun, Junb, Nfkb1, and Sp1. The remaining nine represent new candidates for future studies (Atf1, Irf3, Klf5, Klf6, Mef2d, Nfyb, Nr2f6, Stat3, and Nr4a1). Conspicuously absent is CREB (Creb1), which has been widely proposed to mediate vasopressin-induced regulation of Aqp2 gene transcription (Nielsen S, Frokiaer J, Marples D, Kwon TH, Agre P, Knepper MA. Physiol Rev 82: 205 244, 2002; Kortenoeven ML, Fenton RA. Biochim Biophys Acta 1840: 1533 1549, 2014; Bockenhauer D, Bichet DG. Nat Rev Nephrol 11: 576 588, 2015; Pearce D, Soundararajan R, Trimpert C, Kashlan OB, Deen PM, Kohan DE. Clin J Am Soc Nephrol 10: 135 146, 2015). Instead, another CREB-like TF, Atf1, ranked fourth among all TFs. RNA sequencing time-course experiments showed a rapid increase in Aqp2 mRNA, within 3 h of vasopressin exposure. This response was matched by an equally rapid increase in the abundance of the mRNA coding for Cebpb, which we have shown by chromatin immunoprecipitation-sequencing studies to bind downstream from the Aqp2 gene. The identified TFs provide a roadmap for future studies to understand regulation of Aqp2 gene expression. NEW & NOTEWORTHY Abetted by the advent of systems biology-based ("-omics") techniques in the 21st century, there has been a massive expansion of published data relevant to virtually every physiological question. The authors have developed a large-scale data integration approach based on the application of Bayes ' theorem. In the current work, they integrated 12 different-omics data sets to identify the transcription factors most likely to mediate vasopressin-dependent regulation of transcription of the aquaporin-2 gene.
KW - Bayes theorem
KW - aquaporin-2
KW - collecting duct
KW - kidney
KW - transcription
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U2 - 10.1152/AJPRENAL.00204.2021
DO - 10.1152/AJPRENAL.00204.2021
M3 - Article
C2 - 34308668
AN - SCOPUS:85115161123
SN - 0363-6127
VL - 321
SP - F389-F401
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 3
ER -