 Solution

It is a useful depletion control, but not an automatically modification-free negative control. A nominal knockout may retain functional products, and loss of one writer does not establish absence of every relevant RNA modification. Calling the sample completely negative requires independent validation of the molecular state being used as ground truth.

This distinction has direct experimental support: alternatively spliced functional METTL3 products have been found in some nominal knockout lines.^[ref] That result identifies a possible failure mode; it does not prove that this particular sample has the same defect. A modification-free reference preparation and an independent chemical measurement would strengthen the interpretation.