X. Shawn Liu
Columbia University, NY·Neuroscience
Some brain diseases are driven not by missing genes but by genes that are switched off, or switched off wrongly. DNA methylation is a chemical tag on DNA that can silence a gene without changing its sequence.
- Fields
Neuroscience
Genetics
Biomedical Engineering
- Topics
Rett syndrome
X chromosome inactivation
amyotrophic lateral sclerosis
- Grants
- 2 known grants, through Jun 2028
What they work on
- Test whether reactivating the healthy MECP2 copy on the silenced X chromosome, by removing promoter methyl tags with dCas9-Tet1, rescues Rett syndrome symptoms in female mouse models.
- Measure how efficiently Mecp2 is reactivated in the brain using reporter mice that glow when the gene turns on, comparing a Cre-dependent dCas9-Tet1 mouse line with a compact dCasMini-Tet1 editor delivered in a single AAV9 virus.
- Edit methylation of the C9orf72 G4C2 repeats and nearby CpG islands with dCas9-TET1 or dCas9-DNMT3 in patient iPSC-derived motor and cortical neurons and in C9orf72 transgenic mice, then measure the effects on disease features.
- Identify methylation and gene-activity changes linked to ALS/FTD onset by single-cell methylation and RNA sequencing of affected and unaffected brain regions, and of skin-derived neurons from the same patients before and after symptoms.
More about the research
Both projects use DNA methylation editing tools: a disabled CRISPR protein (dCas9) that is steered to a chosen gene by a guide RNA (sgRNA) and carries an enzyme that adds or removes methyl tags. With these tools, the lab asks whether resetting methylation at a disease gene can reveal how the disease works and point toward treatment.
Why it matters
Rett syndrome and C9orf72-linked ALS/FTD currently lack effective treatments. Showing that methylation editing can turn the silenced healthy MECP2 gene back on and rescue symptoms in mice could pave the way toward clinical trials in girls with Rett syndrome and other X-linked disorders. Defining how C9orf72 methylation shapes disease could reveal protective factors and test methylation editing as a therapy for the most common genetic cause of ALS/FTD.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Bruce Armitage
Carnegie Mellon University, PA·Chemistry
Design fluorescent peptide nucleic acid (PNA) probes that bind unmodified C9orf72 repeat RNAs, so these RNAs can be seen in biomolecular condensates by microscopy.
Jailson Brito Querido
University of Michigan, MI·Biochemistry
Determine how expanded GGGGCC repeats in C9orf72 mRNA physically engage the ribosome to trigger non-AUG start site selection, using cryo-electron microscopy with biochemical and genetic approaches.
Lanlan Shen
Baylor College of Medicine, TX·Genetics
Use inducible dCas9-SunTagTET1 mice, which carry a DNA-targeting CRISPR tool linked to a methylation-removing enzyme, to remove DNA methylation precisely at chosen genes in living animals.
The school
Columbia University: 89 labs on PI Pages, $1.4B a year on research, 625 research doctorates a year.
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