TY - JOUR
T1 - Inferring upstream regulatory genes of FOXP3 in human regulatory T cells from time-series transcriptomic data
AU - Magni, Stefano
AU - Sawlekar, Rucha
AU - Capelle, Christophe M.
AU - Tslaf, Vera
AU - Baron, Alexandre
AU - Zeng, Ni
AU - Mombaerts, Laurent
AU - Yue, Zuogong
AU - Yuan, Ye
AU - Hefeng, Feng Q.
AU - Gonçalves, Jorge
N1 - Acknowledgements
We thank Luxembourg Red Cross and anonymous blood donors for their support. This work was supported by the Luxembourg National Research Fund (FNR) CORE grant, ref CORE/14/BM/8231540/GeDES (J.G. and F.Q.H.). S.M. and C.M.C. were supported in part via the FNR PRIDE DTU CriTiCS, ref 15/10907093. F.Q.H. was also partly supported by the Luxembourg Personalized Medicine Consortium (PMC/2018/01), FNR individual AFR (9989160), AFR-RIKEN bilateral program TregBAR (11228353) and PRIDE DTU NextImmune, ref 15/11012546. V.T. and F.Q.H. were supported via the PRIDE DTU i2TRON, ref 19/14254520. The authors would like to thank Anthony Haynes from Frontinus, for his help and gui- dance in scientific writing and editing of this manuscript. We also acknowledge the National Cytometry Platform (NCP) for assistance with the generation of cytometry data.
© 2024. The Author(s).
PY - 2024/5/29
Y1 - 2024/5/29
N2 - The discovery of upstream regulatory genes of a gene of interest still remains challenging. Here we applied a scalable computational method to unbiasedly predict candidate regulatory genes of critical transcription factors by searching the whole genome. We illustrated our approach with a case study on the master regulator FOXP3 of human primary regulatory T cells (Tregs). While target genes of FOXP3 have been identified, its upstream regulatory machinery still remains elusive. Our methodology selected five top-ranked candidates that were tested via proof-of-concept experiments. Following knockdown, three out of five candidates showed significant effects on the mRNA expression of FOXP3 across multiple donors. This provides insights into the regulatory mechanisms modulating FOXP3 transcriptional expression in Tregs. Overall, at the genome level this represents a high level of accuracy in predicting upstream regulatory genes of key genes of interest.
AB - The discovery of upstream regulatory genes of a gene of interest still remains challenging. Here we applied a scalable computational method to unbiasedly predict candidate regulatory genes of critical transcription factors by searching the whole genome. We illustrated our approach with a case study on the master regulator FOXP3 of human primary regulatory T cells (Tregs). While target genes of FOXP3 have been identified, its upstream regulatory machinery still remains elusive. Our methodology selected five top-ranked candidates that were tested via proof-of-concept experiments. Following knockdown, three out of five candidates showed significant effects on the mRNA expression of FOXP3 across multiple donors. This provides insights into the regulatory mechanisms modulating FOXP3 transcriptional expression in Tregs. Overall, at the genome level this represents a high level of accuracy in predicting upstream regulatory genes of key genes of interest.
KW - Humans
KW - Forkhead Transcription Factors/genetics
KW - T-Lymphocytes, Regulatory/immunology
KW - Transcriptome/genetics
KW - Computational Biology/methods
KW - Gene Expression Regulation/genetics
KW - Gene Expression Profiling/methods
KW - Genes, Regulator/genetics
UR - http://www.scopus.com/inward/record.url?scp=85194833761&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/38811598
U2 - 10.1038/s41540-024-00387-9
DO - 10.1038/s41540-024-00387-9
M3 - Article
C2 - 38811598
SN - 2056-7189
VL - 10
SP - 59
JO - npj Systems Biology and Applications
JF - npj Systems Biology and Applications
IS - 1
ER -