Scavenger Cells Failure to Maintain Systemic RNA Homeostasis Causes Epigenetically Inherited Germline Tumors

Area of Science:

• Developmental Biology
• Epigenetics
• Cancer Biology

Background:

• Epigenetic disruptions can alter cell fate and development.
• Somatic dysfunction in parents potentially leading to multi-generational susceptibility to tumorigenesis is unknown.
• In C. elegans, somatic cells do not divide, but germline tumors can form.

Purpose of the Study:

• To investigate if somatic cell dysfunction in mothers can cause heritable germline tumorigenesis in C. elegans.
• To elucidate the mechanisms underlying transgenerational tumor susceptibility.

Main Methods:

• Disruption of coelomocytes (somatic scavenger cells) in C. elegans mothers.
• Analysis of germline integrity and RNA homeostasis in subsequent generations.
• Assessment of transcriptional and small RNA profiles.

Main Results:

• Disruption of maternal coelomocytes provokes heritable germline tumorigenesis in genetically wild-type descendants for multiple generations.
• Coelomocyte dysfunction impairs RNA clearance, disrupting systemic RNA homeostasis.
• Excess somatic RNAs access the germline, causing widespread dysregulation and loss of germline identity.

Conclusions:

• Systemic RNA homeostasis is crucial for preventing heritable tumorigenesis.
• Small RNAs appear to be the agents carrying pathological information across generations.
• Somatic cell dysfunction can have profound multi-generational impacts on germline integrity and cancer susceptibility.