Research
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Gene Dosage and Cell-Type-Specific Regulation of Brain Development and Dysfunction
We are broadly interested in how gene dosage and cell-type-specific mechanisms regulate normal brain development and how gene dosage imbalance causes human neurodevelopmental and neuropsychiatric disorders, with a special focus on transcriptional regulators. The human brain is highly sensitive to the proper dosage of specific dose-sensitive genes, such as those involved in copy number variations (CNVs). Little is known about how these dose-sensitive genes regulate brain development at the molecular, cellular, and circuit levels.
Our platform focuses on syndromic autism spectrum disorders with a focus on Smith-Magenis syndrome (SMS), associated with intellectual disability, epilepsy, obesity, autism, and neuropsychiatric features. SMS is caused by 17p11.2 deletion or loss of the Retinoic Acid Induced 1 (RAI1) gene, providing an excellent genetic entry point to understand how CNVs control brain development and function. The Huang lab uses genetic, molecular, cell biological, and modern stem cell and neuroscience techniques to (1) determine the molecular and neurobiological functions of RAI1/17p11.2 deletions, and (2) develop disease-modifying stem cell, drug, and gene therapies to reverse debilitating symptoms associated with syndromic autism spectrum disorders.
We have pioneered several domains in SMS research, including building the first conditional Rai1 knockout mouse model (Huang WH et al., Neuron, 2016), developing the first CRISPRa gene therapy (Chang HC et al., J Biol Chem., 2023) and pharmacological therapy (Javed S et al., eLife, 2023) for SMS mice, and engineering the first human 2D and 3D neural models of SMS (Lee YJ et al., Am J Hum Genet., 2025). Here are our current interests:
Molecular and Cellular Pathogenic Mechanisms of Syndromic Autism Spectrum Disorders:
Our platform focuses on syndromic autism spectrum disorders with a focus on Smith-Magenis syndrome (SMS), associated with intellectual disability, epilepsy, obesity, autism, and neuropsychiatric features. SMS is caused by 17p11.2 deletion or loss of the Retinoic Acid Induced 1 (RAI1) gene, providing an excellent genetic entry point to understand how CNVs control brain development and function. The Huang lab uses genetic, molecular, cell biological, and modern stem cell and neuroscience techniques to (1) determine the molecular and neurobiological functions of RAI1/17p11.2 deletions, and (2) develop disease-modifying stem cell, drug, and gene therapies to reverse debilitating symptoms associated with syndromic autism spectrum disorders.
We have pioneered several domains in SMS research, including building the first conditional Rai1 knockout mouse model (Huang WH et al., Neuron, 2016), developing the first CRISPRa gene therapy (Chang HC et al., J Biol Chem., 2023) and pharmacological therapy (Javed S et al., eLife, 2023) for SMS mice, and engineering the first human 2D and 3D neural models of SMS (Lee YJ et al., Am J Hum Genet., 2025). Here are our current interests:
Molecular and Cellular Pathogenic Mechanisms of Syndromic Autism Spectrum Disorders:
- How does gene dosage imbalance affect molecular and cellular aspects of neuronal development and function?
- What are the neurobehavioural and neural circuit functions of RAI1-containing chromatin complex?
- Building novel disease models of syndromic autism spectrum disorders
- How to correct disrupted molecular signalling pathways and reverse symptoms of syndromic autism spectrum disorders?
- Can increasing the expression levels of disease-causing genes at transcriptional and post-translational levels alleviate disease features?
For our published work, please visit the PUBLICATIONS page