Figure 2: Partial lac repressor-mediated transcriptional repression of mHtt reduces somatic instability in Htt’s CAG repeat in the livers of HttQ140 mice.
A) Schematic of study design indicating when mice in 3 cohorts were treated with IPTG, reducing LacR-mediated repression of the HttQ140 allele. B) Overview of the mechanisms of action of the lac repressor system. C) Protein knockdown at sacrifice: wtHTT is unaffected by the lac repressor (p = 0.52), while mHTT levels are reduced (46%, p < 0.0001). D) Knockdown of total Htt mRNA from liver from replicate mouse experiment (27%, p = 0.018; NB, only mHTT is repressed, so this non-allele selective mRNA assay represents an under-estimate of mHTT-selective knockdown). E) Somatic instability is reduced via partial LacR-mediated repression of mHtt, with greater suppression of instability given longer suppression durations. F) Exemplar traces of repressed and unrepressed mice. For box and whisker plots, each data point is shown, and the horizontal lines indicate the 25th, 50th and 75th percentiles of the data, with vertical lines indicating the range, with outliers detached from the vertical lines.