Fireworks

Fireworks constructs coessential gene networks from genome-scale fitness screening data to elucidate regulatory modules and master regulators that govern cellular responses to proteotoxic, oxidative, hypoxic, and genotoxic stress.

Key Features:

• Coessential Gene Network Construction: Builds networks of coessential gene relationships by analyzing genome-scale fitness screening data from 625 cancer cell lines.
• Functional Module Organization: Organizes the stress response into distinct functional modules and identifies genes that connect modules.
• Master Regulator Identification: Centers networks around master regulators that govern responses to proteotoxic, oxidative, hypoxic, and genotoxic stresses.
• Mechanistic Insight into Module Dependence: Reveals mechanisms underlying cellular dependence on individual stress response modules by mapping interdependencies among essential genes.
• Discovery of Novel Regulators: Detects previously unannotated stress-inducible regulators, exemplified by identification of HAPSTR (C16orf72) as a regulator of the E3 ligase HUWE1.

Scientific Applications:

• Network interrogation using genetic screens: Uses unbiased genome-scale fitness screening data to map functional relationships within cellular networks.
• Tumorigenesis research: Identifies stress response modules and regulators relevant to cancer cell fitness across diverse cancer cell lines.
• Neurodegeneration studies: Maps stress-related dependencies and regulators relevant to neurodegenerative disease mechanisms.
• Aging research: Characterizes cellular stress-response modules and dependencies implicated in aging.
• Therapeutic target identification: Facilitates identification of candidate targets within stress response modules and their regulators.

Methodology:

Integrates genome-scale fitness screening data from 625 cancer cell lines with computational network construction and analysis to build coessential gene networks, map essential genes and their interdependencies, define functional modules, identify master regulators, and detect regulators such as HAPSTR (C16orf72) acting on HUWE1.