Suppression of Huntington’s disease somatic instability by transcriptional repression and direct CAG repeat binding

Huntington’s disease arises from a CAG expansion in the huntingtin gene beyond a critical threshold. Current therapeutics primarily aim to reduce toxicity by lowering levels of mutant HTT mRNA and protein. Genetic data support a role for somatic instability in HTT’s CAG repeat as a driver of age of motor dysfunction onset, but currently, the relationship between instability and HTT lowering remains unexplored. Here, we investigate various HTT-lowering modalities to establish the relationship between HTT lowering and instability in Huntington’s disease knock-in mice. We find that repressing transcription of mutant Htt reduces instability, using genetic and pharmacological approaches. Remarkably, zinc finger proteins that target CAG repeats, but lack a repressive domain, protect from somatic instability despite not reducing HTT mRNA or protein levels. These results suggest that DNA-targeted HTT-lowering treatments may have advantages compared to other HTT-lowering approaches, and that ste..., All data was either collected directly by the Carroll lab at Western Washington University and University of Washington, or sent to us by collaborating labs where data was collected: Evotec SE, Hamburg, Germany; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Ionis Pharmaceuticals; CHDI Management, Inc.; Center for Genomic Medicine, Massachusetts General Hospital. 
The data is in its raw form, with the exception of somatic instability data, which has been processed through an R script (available on Zenodo) to generate expansion indices for each mouse., , # Data from: Suppression of Huntington’s disease somatic instability by transcriptional repression and direct CAG repeat binding

[https://doi.org/10.5061/dryad.0k6djhb98](https://doi.org/10.5061/dryad.0k6djhb98)

## Description of the data and file structure

This data collections contains all data associated with the attached manuscript. 

### Files and variables

#### File: Source_Data.xlsx

**Description:** The main spreadsheet contains all the raw data from the associated manuscript. It is divided into pages, one for each figure. The page names start with the associated figure number. 

##### Variables

1b - PAF protein: Western blot data from our peripheral ASO follow-up study (PAF)

* Blot: Denotes which gel the samples were run on
* Genotype: The genotype of the associated mouse
* Sample: The internal mouse ID, used to differentiate individual mice
* Treatment: Denotes which experimental treatment the associated mouse received
* TPS: Raw value of the total protein stain lane cor...,