PT  - JOURNAL ARTICLE
AU  - Madhur Parihar
AU  - Liat Bendelac-Kapon
AU  - Michal Gur
AU  - Abha Belorkar
AU  - Sirisha Achanta
AU  - Keren Kinberg
AU  - Rajanikanth Vadigepalli
AU  - Abraham Fainsod
TI  - Asymmetric robustness in the feedback control of the retinoic acid network response to environmental disturbances
AID  - 10.1101/2020.07.15.203794
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.15.203794
4099  - http://biorxiv.org/content/early/2020/12/24/2020.07.15.203794.short
4100  - http://biorxiv.org/content/early/2020/12/24/2020.07.15.203794.full
AB  - Robustness is a characteristic of regulatory pathways to ensure signal consistency in light of environmental changes or genetic polymorphisms. The retinoic acid (RA) pathway is a central developmental and tissue homeostasis regulatory signal, strongly dependent on nutritional sources of retinoids and affected by exogenous chemicals. We performed transient physiological RA signaling disturbances during embryogenesis followed by kinetic transcriptomic and high-throughput qPCR analysis of the recovery. Unbiased pattern analysis identified the RA metabolic network as the main regulated module aimed at achieving signaling robustness. We used a principal trajectory-based analysis of the clutch-dependent variability and organized the results into a robustness efficiency matrix comparing the RA feedback regulation and hox gene expression (RA targets). We found the feedback autoregulation to be sensitive to the direction of the RA perturbation: RA knockdown exhibited an upper response threshold, whereas RA addition did not activate a feedback response below a minimum threshold. These results demonstrate an asymmetric capacity for robust feedback control of the RA signal during early embryogenesis, probably based on genetic polymorphisms, likely a significant contributor to the manifestation of developmental defects.Competing Interest StatementThe authors have declared no competing interest.COMPACTComparative Matrix of Pattern CountsDEAB4-diethylaminobenzaldehydePCAPrincipal Component AnalysisPCRPolymerase Chain ReactionRAretinoic acidWGCNAWeighted Gene Coexpression Network Analysis